Pyrrolopyridazines as potassium ion channel inhibitors

ABSTRACT

A compound of formula (I) wherein A, R 1 , R 3 , and R 24  are described herein. The compounds are useful as inhibitors of potassium channel function and in the treatment of arrhythmia, I Kur -associated disorders, and other disorders mediated by ion channel function.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/775,742 filed Mar. 11, 2013, whose contents are hereby incorporatedby reference.

FIELD OF THE INVENTION

The present invention provides for pyrrolopyridazines useful asinhibitors of potassium channel function (especially inhibitors of theK_(v)1 subfamily of voltage gated K⁺ channels, more especiallyinhibitors of K_(v)1.5 (which have been linked to the ultra-rapidlyactivating delayed rectifier K⁺ current I_(Kur)), and/or K_(v)1.3channels, and/or K_(v)1.1 channels) and to pharmaceutical compositionscontaining such compounds. The present invention further provides formethods of using such compounds in the treatment and prevention ofarrhythmia, I_(Kur)-associated disorders, and other disorders mediatedby ion channel function.

BACKGROUND OF THE INVENTION

The ultra-rapidly activating delayed rectifier K⁺ current (I_(Kur)) isbelieved to represent the native counterpart to a cloned potassiumchannel designated K_(v)1.5 and, while present in human atrium, itappears to be absent in human ventricle. Furthermore, because of itsrapidity of activation and limited slow inactivation, I_(Kur) isbelieved to contribute significantly to repolarization in human atrium.Consequently, a specific blocker of I_(Kur), that is a compound whichblocks K_(v)1.5, would overcome the short coming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular repolarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III antiarrhythmicagents. (Antiarrhythmic agents of Class III are drugs that cause aselective prolongation of the duration of the action potential withoutsignificant cardiac depression.)

Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves' ophthalmopathy and asthma. Although the underlyingpathogenesis of each of these conditions may vary, they have in commonthe appearance of a variety of auto-antibodies and self-reactivelymphocytes. Such self-reactivity may be due, in part, to a loss of thehomeostatic controls under which the normal immune system operates.Similarly, following a bone-marrow or an organ transplantation,lymphocytes recognize the foreign tissue antigens and begin to produceimmune mediators which lead to graft rejection or graft-vs-hostrejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAIDs act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion in whichboth the normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb to infection as they are to their autoimmune disease.

Cyclosporin A, which was approved by the US FDA in 1983 is currently theleading drug used to prevent rejection of transplanted organs. In 1993,FK-506 (PROGRAF®) was approved by the US FDA for the prevention ofrejection in liver transplantation. Cyclosporin A and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, Cyclosporin A was approved by the US FDA for the treatment ofsevere psoriasis and has been approved by European regulatory agenciesfor the treatment of atopic dermatitis. Though these agents areeffective in fighting transplant rejection, Cyclosporin A and FK-506 areknown to cause several undesirable side effects includingnephrotoxicity, neurotoxicity, and gastrointestinal discomfort.Therefore, a selective immunosuppressant without these side effectsstill remains to be developed. Potassium channel inhibitors as describedhere promise to be the solution to this problem, since inhibitors ofK_(v)1.3, for example, are immunosuppressive. See Wulff et al.,“Potassium channels as therapeutic targets for autoimmune disorders”,Curr. Opin. Drug Discov. Devel., 6(5):640-647 (September 2003); Shah etal., “Immunosuppressive effects of a K_(v)1.3 inhibitor”, Cell Immunol.,221(2):100-106 (Feb. 2003); Hanson et al., “UK-78,282, a novelpiperidine compound that potently blocks the K_(v)1.3 voltage-gatedpotassium channel and inhibits human T cell activation”, Br. J.Pharmacol., 126(8):1707-1716 (April 1999).

Inhibitors of K_(v)1.5 and other K_(v)1.x channels stimulategastrointestinal motility. Thus, the compounds of the invention arebelieved to be useful in treating motility disorders such as refluxesophagitis. See Frey et al., “Blocking of cloned and native delayedrectifier K channels from visceral smooth muscles by phencyclidine”,Neurogastroenterol. Motil., 12(6):509-516 (December 2000); Hatton etal., “Functional and molecular expression of a voltage-dependent K(+)channel (K_(v)1.1) in interstitial cells of Cajal”, J. Physiol., 533(Pt2):315-327 (Jun. 1, 2001); Vianna-Jorge et al., “Shaker-type K_(v)1channel blockers increase the peristaltic activity of guinea-pig ileumby stimulating acetylcholine and tachykinins release by the entericnervous system”, Br. J. Pharmacol., 138(1):57-62 (January 2003); Koh etal., “Contribution of delayed rectifier potassium currents to theelectrical activity of murine colonic smooth muscle”, J. Physiol.,515(Pt. 2):475-487 (Mar. 1, 1999).

Inhibitors of K_(v)1.5 relax pulmonary artery smooth muscle. Thus, thecompounds of the invention are believed to be useful in treatinghypertension and otherwise improving vascular health. See Davies et al.,“K_(v) channel subunit expression in rat pulmonary arteries”, Lung,179(3):147-161 (2001), Epub. Feb. 4, 2002; Pozeg et al., “In vivo genetransfer of the O2-sensitive potassium channel K_(v)1.5 reducespulmonary hypertension and restores hypoxic pulmonary vasoconstrictionin chronically hypoxic rats”, Circulation, 107(15):2037-2044 (Apr. 22,2003), Epub. Apr. 14, 2003.

Inhibitors of K_(v)1.3 increase insulin sensitivity. Hence, thecompounds of the invention are believed to be useful in treatingdiabetes. See Xu et al., “The voltage-gated potassium channel K_(v)1.3regulates peripheral insulin sensitivity”, Proc. Natl. Acad. Sci.U.S.A., 101(9):3112-3117 (Mar. 2, 2004), Epub. Feb. 23, 2004; MacDonaldet al., “Members of the K_(v)1 and K_(v)2 voltage-dependent K(+) channelfamilies regulate insulin secretion”, Mol. Endocrinol., 15(8):1423-1435(August 2001); MacDonald et al., “Voltage-dependent K(+) channels inpancreatic beta cells: role, regulation and potential as therapeutictargets”, Diabetologia, 46(8): 1046-1062 (August 2003), Epub. Jun. 27,2003.

Stimulation of K_(v)1.1 is believed to reduce seizure activity byhyperpolarizing neurons. Thus, the compounds of the invention arebelieved to be useful in treating seizures, including seizuresassociated with epilepsy and other neurological diseases. See Rho etal., “Developmental seizure susceptibility of kv1.1 potassium channelknockout mice”, Dev. Neurosci., 21(3-5):320-327 (November 1999); Colemanet al., “Subunit composition of K_(v)1 channels in human CNS”, J.Neurochem., 73(2):849-858 (August 1999); Lopantsev et al.,“Hyperexcitability of CA3 pyramidal cells in mice lacking the potassiumchannel subunit K_(v)1.1”, Epilepsia, 44(12):1506-1512 (December 2003);Wickenden, “Potassium channels as anti-epileptic drug targets”,Neuropharmacology, 43(7):1055-1060 (December 2002).

Inhibition of K_(v)1.x channels improves cognition in animal models.Thus, the compounds of the invention are believed to be useful inimproving cognition and/or treating cognitive disorders. See Cochran etal., “Regionally selective alterations in local cerebral glucoseutilization evoked by charybdotoxin, a blocker of centralvoltage-activated K+-channels”, Eur. J. Neurosci., 14(9):1455-1463(November 2001); Kourrich et al., “Kaliotoxin, a K_(v)1.1 and K_(v)1.3channel blocker, improves associative learning in rats”, Behav. BrainRes., 120(1):35-46 (Apr. 8, 2001).

SUMMARY OF THE INVENTION

In accordance with the present invention, acyclic compounds and relatedcompounds are provided that have the general structure of formula (I):

wherein A, R¹, R³, and R₂₄ are defined below.

By use of a respective effective amount of at least one compounddescribed herein, provided are methods of treating (includingameliorating), reducing the risk of or preventing arrhythmias, atrialfibrillation, atrial flutter, supraventricular arrhythmias,gastrointestinal disorders (such as reflux esophagitis or a motilitydisorder), inflammatory or immunological disease (such as chronicobstructive pulmonary disease), diabetes, cognitive disorders, migraine,epilepsy, hypertension, or treating I_(Kur)-associated conditions, orcontrolling heart rate.

Also provided are pharmaceutical compositions comprising atherapeutically effective amount of at least one compound describedherein and a pharmaceutically acceptable vehicle or carrier thereof.Such compositions can further comprise one or more other agent(s). Forexample, at least one other anti-arrhythmic agent (such as sotalol,dofetilide, diltiazem or Verapamil), or at least one calcium channelblocker, or at least one anti-platelet agent (such as clopidogrel,cangrelor, ticlopidine, CS-747, ifetroban and aspirin), or at least oneanti-hypertensive agent (such as a beta adrenergic blocker, ACEinhibitor (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, orlisinopril), A II antagonist, ET antagonist, Dual ET/A II antagonist, orvasopepsidase inhibitor (e.g., omapatrilat or gemopatrilat)), or atleast one anti thrombotic/anti thrombolytic agent (such as tPA,recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors(such as apixaban), factor XIa inhibitors or thrombin inhibitors), or atleast one anti coagulant (such as warfarin or a heparin), or at leastone HMG-CoA reductase inhibitor (pravastatin, lovastatin, atorvastatin,simvastatin, NK-104 or ZD-4522), or at least one anti diabetic agent(such as a biguanide or a biguanide/glyburide combination), or at leastone thyroid mimetic, or at least one mineralocorticoid receptorantagonist (such as spironolactone or eplerinone), or at least onecardiac glycoside (such as digitalis or ouabain).

Another aspect of this invention is directed to methods of treating,inhibiting, or ameliorating the symptoms of a disease or disorder thatis modulated or otherwise affected by inhibitors of potassium channelfunction (especially inhibitors of the K_(v)1 subfamily of voltage gatedK⁺ channels, more especially inhibitors of K_(v)1.5 (which have beenlinked to the ultra-rapidly activating delayed rectifier K⁺ currentI_(Kur)), and/or K_(v)1.3 channels, and/or K_(v)1.1 channels),comprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound of the present invention or an individualisomer or mixture of isomers or a pharmaceutically acceptable saltthereof.

Another aspect of this invention is directed to methods of treating,inhibiting, or ameliorating arrhythmia, or maintaining normal sinusrhythm comprising administering to a subject in need thereof atherapeutically effective amount of a compound of the present inventionor an individual isomer or mixture of isomers or a pharmaceuticallyacceptable salt thereof.

Another aspect of this invention is directed to methods of controllingheart rate, comprising administering to a subject in need thereof atherapeutically effective amount of a compound of the present inventionor an individual isomer or mixture of isomers or a pharmaceuticallyacceptable salt thereof.

DEFINITIONS

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms,1 to 6 carbon atoms, 1 to 4 carbon atoms, or 1 to 3 carbon atoms, suchas methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl,hexyl, heptyl, octyl, or any subset of the foregoing. The term“substituted alkyl” refers to alkyl groups substituted with one or moregroups (such as by groups described above in the definition of R¹⁰),such as selected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone double carbon to carbon bond (either cis or trans), such as ethenyl.The term “substituted alkenyl” refers to alkenyl groups substituted withone or more groups (such as by groups described above in the definitionof R¹⁰), such as selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane and sulfonyl, or any subset of the foregoing.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone triple carbon to carbon bond, such as ethynyl. The term “substitutedalkynyl” refers to alkynyl groups substituted with one or more groups(such as by groups described above in the definition of R¹⁰), such asselected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “aryl” refers to aromatic homocyclic (i.e., hydrocarbon) mono-,bi- or tricyclic ring-containing groups such as having 6 to 12 memberssuch as phenyl, naphthyl and biphenyl. Phenyl is an example of an arylgroup. The term “substituted aryl” refers to aryl groups substitutedwith one or more groups (such as by groups described above in thedefinition of R¹⁰), such as selected from alkyl, substituted alkyl,alkenyl (optionally substituted), aryl (optionally substituted),heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl, (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane and sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “cycloalkyl” refers to mono-, bi- or tri-homocyclic ring groupsof 3 to 15 carbon atoms which are, respectively, fully saturated andpartially unsaturated. The rings of multi-ring cycloalkyl groups may befused, bridged and/or joined through one or more spiro unions. The term“substituted cycloalkyl” refers to a cycloalkyl group substituted withone or more groups (such as by groups described above in the definitionof R¹⁰), such as selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane and sulfonyl, or any subset of the foregoing.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The term “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups, for example CF₃,having the specified number of carbon atoms, substituted with 1 or morehalogen, up to and including perhalo alkyls (where all hydrogen atomsare replaced with a halogen).

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially or completelyunsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclicgroups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring memberbicyclic, or 10 to 20 ring member tricyclic ring systems, such as, incertain embodiments, a monocyclic or bicyclic ring containing a total of3 to 10 ring atoms) which have at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be fused, bridged and/or joinedthrough one or more spiro unions.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl,tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls(such as 6-azabicyclo[3.2.1]octane), azaspiroalkyls (such as 1,4dioxa-8-azaspiro[4.5]decane), imidazopyridinyl (such asimidazo[1,5-a]pyridin-3-yl), triazolopyridinyl (such as1,2,4-triazolo[4,3-a]pyridin-3-yl), and hexahydroimidazopyridinyl (suchas 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-3-yl),

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups (such as by groups described above in the definition ofR¹⁰), such as selected from alkyl, substituted alkyl, alkenyl, oxo,aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo(optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amido,amino, substituted amino, lactam, urea, urethane, sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “alkanoyl” refers to alkyl group (which may be optionallysubstituted as described above) linked to a carbonyl group (i.e.,—C(O)-alkyl). Similarly, the term “aroyl” refers to an aryl group (whichmay be optionally substituted as described above) linked to a carbonylgroup (i.e., —C(O)-aryl).

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

Compounds described herein may form salts or solvates which are alsowithin the scope of this invention. Reference to a compound describedherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic and/or basic salts formed with inorganic and/or organic acids andbases. In addition, when a compound described herein contains both abasic moiety and an acidic moiety, zwitterions (“inner salts”) may beformed and are included within the term “salt(s)” as used herein. In oneembodiment, the salts are pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable), although other salts are also useful, e.g.,in isolation or purification steps which may be employed duringpreparation. Salts of the compounds described herein may be formed, forexample, by reacting a compound with an amount of acid or base, such asan equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The present invention is intended to cover the compounds in theirneutral state, salts of those compounds, or mixtures of the compounds intheir neutral state with one or more salt forms, or mixtures of saltforms.

The compounds described herein which contain a basic moiety may formsalts with a variety of organic and inorganic acids. Exemplary acidaddition salts include acetates (such as those formed with acetic acidor trihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds described herein which contain an acidic moiety may formsalts with a variety of organic and inorganic bases. Exemplary basicsalts include ammonium salts, alkali metal salts such as sodium,lithium, and potassium salts, alkaline earth metal salts such as calciumand magnesium salts, salts with organic bases (for example, organicamines) such as benzathines, dicyclohexylamines, hydrabamines (formedwith N,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g., methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g., decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g., benzyl and phenethyl bromides), and others.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula (I)) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula (I)with alkyl, alkoxy, or aryl substituted acylating agents employingprocedures known to those skilled in the art to generate acetates,pivalates, methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

-   a) Wermuth, C. G. et al., The Practice of Medicinal Chemistry,    Chapter 31, Academic Press (1996);-   b) Bundgaard, H., ed., Design of Prodrugs, Elsevier (1985);-   c) Bundgaard, H., Chapter 5, “Design and Application of Prodrugs”,    Krosgaard-Larsen, P. et al., eds., A Textbook of Drug Design and    Development, pp. 113-191, Harwood Academic Publishers (1991); and-   d) Testa, B. et al., Hydrolysis in Drug and Prodrug Metabolism,    Wiley-VCH (2003).

“Pharmaceutically acceptable” refers to those compounds, materials,compositions, and/or dosage forms which are, within the scope of soundmedical judgment, suitable for contact with the tissues of human beingsand animals without excessive toxicity, irritation, allergic response,or other problems or complications commensurate with a reasonablebenefit/risk ratio or which have otherwise been approved by the UnitedStates Food and Drug Administration as being acceptable for use inhumans or domestic animals.

The various compounds described herein, or their pharmaceuticallyacceptable salts, may contain one or more asymmetric centers and maythus give rise to isomers, such as enantiomers, diastereomers, and otherstereoisomeric forms. Such forms may be defined, in terms of absolutestereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.The present invention is meant to include all such possible individualstereoisomers and mixtures thereof, including their racemic andoptically pure enantiomeric or diastereomeric forms. The compounds maybe prepared as racemates and can conveniently be used as such, oroptically active (+) and (−), (R)- and (S)-, or (D)- and (L)-isomers orcorresponding diastereomers may be prepared using chiral synthons orchiral reagents, or they may be resolved from racemic mixtures usingconventional techniques, such as chiral chromatography or reverse phaseHPLC. When the compounds described herein contain olefinic double bondsor other centers of geometric asymmetry, and unless specified otherwise,it is intended that the compounds include both E and Z geometricisomers.

The invention also includes isotopically-labeled compounds of theinvention, wherein one or more atoms is replaced by an atom having thesame atomic number, but an atomic mass or mass number different from theatomic mass or mass number usually found in nature. Examples of isotopessuitable for inclusion in the compounds of the invention includeisotopes of hydrogen, such as ²H or D and ³H or T, carbon such as ¹¹C,¹³C, and ¹⁴C, chlorine, such as ³⁶Cl, fluorine such as ¹⁸F, iodine, suchas ¹²³I and ¹²⁵I, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O,¹⁷O, and ¹⁸O, phosphorus, such as ³²P, and sulfur, such as ³⁵S. Certainisotopically-labeled compounds of the invention, for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, ³H, andcarbon-14, ¹⁴C, are particularly useful for this purpose in view oftheir ease of incorporation and ready means of detection. Substitutionwith heavier isotopes such as deuterium, ²H or D, may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increase in vivo half-life or reduced dosage requirements, andhence may be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O, and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy.

To the extent that compounds described herein, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons) and diastereomeric forms are contemplated within the scope ofthis invention. Individual stereoisomers of the compounds of theinvention may, for example, be substantially free of other isomers, ormay be admixed, for example, as racemates or with all other, or otherselected, stereoisomers.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. The present invention is intended tocover stable compounds.

When any variable (e.g., R¹³) occurs more than one time in anyconstituent or formula for a compound, its definition at each occurrenceis independent of its definition at every other occurrence. Thus, forexample, if a group is shown to be substituted with 0-2 R¹³, then saidgroup may optionally be substituted with up to two R¹³ groups and R¹³ ateach occurrence is selected independently from the definition of R¹³.Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

“Therapeutically effective amount” refers to that amount of a compoundwhich, when administered to a subject, is sufficient to effect treatmentfor a disease or disorder described herein. The amount of a compoundwhich constitutes a “therapeutically effective amount” will varydepending on the compound, the disorder and its severity, and the age ofthe subject to be treated, but can be determined routinely by one ofordinary skill in the art.

“Treating” or “treatment” as used herein covers the treatment,prophylaxis, and/or reducing the risk, of a disease or disorderdescribed herein, or treatment, prophylaxis, or reducing the risk of asymptom of a disease or disorder, in a subject, such as a human, andincludes:

i. inhibiting a disease or disorder, i.e., arresting its development; or

ii. relieving a disease or disorder, i.e., causing regression of thedisorder.

“Subject” refers to a warm blooded animal such as a mammal, such as ahuman, or a human child, which is afflicted with, or has the potentialto be afflicted with one or more diseases and disorders describedherein.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with the present invention, compounds of formula (I) areprovided

or enantiomers, diastereomers, tautomers, prodrugs or salts thereofwherein:

A is —(CH₂)_(m)—R², —CH(R²⁶)—R², —(CH₂)_(n-1)—O—R²,—(CH₂)_(n-1)—NR²⁵—R², —CH(R²⁶)—CO₂—R², or —(CH₂)_(n-1)—NR²⁵—CO₂—R²;

R¹ is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, C₂₋₁₂alkenyl, or C₃₋₁₀ cycloalkyl, wherein the cycloalkyl may be substitutedwith 0-2 R¹³; or

R¹ is

any of which may be substituted with 0-2 R¹³;

R² is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl,tetrahydropyrans, or thiazolyl, any of which are substituted with 0-2R^(2a);

R^(2a), at each occurrence, is independently H, —OH, F, Cl, Br, I, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4- to 12-membered heteroaryl, a 4- to12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C₁₋₁₀ alkyl,—CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴, —NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴,—(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂NR¹⁴R¹⁴,—NR¹⁴SO₂NR¹⁴R¹⁴, —CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴,—SO₂NR¹⁴COR¹⁴, —SO₂NR¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴,—NR¹⁴CONR¹⁴R¹⁴, —C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴ or —NCOR¹⁴, wherein thealkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclylmay be substituted with 0-2 R^(14a), and the heteroaryl and heterocyclylconsist of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, S, or O;

R³ is phenyl, pyridinyl, pyrimidinyl, or dihydropyran, ortetrahydropyran any of which may be substituted with 0-1 R^(3a);

R^(3a) is halo, CN, NH₂, —O—C₁₋₃alkyl, or morpholinyl;

R¹³, at each occurrence, is independently H, —OH, F, Cl, Br, I, CN,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4- to 12-membered heteroaryl, a 4-to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C₁₋₁₀ alkyl,—CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴, —NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴,—(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂NR¹⁴R¹⁴,—NR¹⁴SO₂NR¹⁴R¹⁴, —CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴,—SO₂NR¹⁴COR¹⁴, —SO₂NR¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴,—NR¹⁴CONR¹⁴R¹⁴, —C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴, or —NCOR¹⁴, or OR¹⁴,wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl andheterocyclyl may be substituted with 0-2 R^(14a), and the heteroaryl andheterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, S, or O;

R¹⁴, at each occurrence, is independently selected from hydrogen, C₁₋₁₀alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, a 4- to 12-membered heteroaryl or a4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl may be substituted with 0-3 R^(14a) and theheteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO; or

alternatively, two R¹⁴'s are taken together with the atoms to which theyare attached to form a cyclic ring, wherein the cyclic ring may besubstituted with 0-1 R^(14a) and optionally contain 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO;

R^(14a), at each occurrence, is independently selected from F, Cl, Br,I, C₁₋₁₀ alkyl, haloC₁₋₁₀alkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, a 4- to12-membered heteroaryl, a 4- to 12-membered heterocyclyl, F, Cl, Br, I,—CN, —NO₂, —CO₂R₂₆, —CO₂NR₂₄R₂₄, —OCF₃, —OR₂₅, ═O, —CONR²⁴R²⁴, —COR²⁴,—SO₂R²⁴, NR²⁴R²⁴, —NR²⁴CO₂R²⁴, —SO₂NR²⁴R²⁴, or C₆₋₁₀arylC₁₋₁₀alkyl,wherein the heteroaryl and heterocyclyl consist of carbon atoms and 1,2, 3, or 4 heteroatoms independently selected from the group consistingof N, S, or O;

R²⁴, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁵, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁶, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

m is 0 to 4;

n is 0 to 4; and

n−1 is 2 to 4.

In accordance with the present invention, compounds of formula (I) areprovided

or enantiomers, diastereomers, tautomers, prodrugs or salts thereofwherein:

A is —(CH₂)_(m)—R², —CH(R²⁶)—R², —(CH₂)_(n-1)—O—R²,—(CH₂)_(n-1)—NR²⁵—R², —CH(R²⁶)—CO₂—R², or —(CH₂)_(n-1)—NR²⁵—CO₂—R²;

R¹ is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, C₂₋₁₂alkenyl, or C₃₋₁₀ cycloalkyl, wherein the cycloalkyl may be substitutedwith 0-2 R¹³; or

R¹ is

any of which may be substituted with 0-2 R¹³;

R² is phenyl, cyclopentyl, cyclohexyl, pyridinyl, pyrazinyl,pyridazinyl, pyrimidinyl, piperidinyl, pyridinone, pyrrolidinyl,tetrahydropyrans, or thiazolyl, any of which are substituted with 0-2R^(2a);

R^(2a), at each occurrence, is independently H, —OH, F, Cl, Br, I, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₂ alkenyl,C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4- to 12-membered heteroaryl, a 4- to12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C₁₋₁₀ alkyl,—CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴, —NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴,—(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂NR¹⁴R¹⁴,—NR¹⁴SO₂NR¹⁴R¹⁴, —CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴,—SO₂NR¹⁴COR¹⁴, —SO₂NR¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴,—NR¹⁴CONR¹⁴R¹⁴, —C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴, or —NCOR¹⁴, wherein thealkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclylmay be substituted with 0-2 R^(14a), and the heteroaryl and heterocyclylconsist of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, S, or O;

R³ is phenyl, pyridinyl, pyrimidinyl, or dihydropyran, ortetrahydropyran any of which may be substituted with 0-1 R^(3a);

R^(3a) is halo, CN, NH₂, —O—C₁₋₃alkyl, or morpholinyl;

R¹³, at each occurrence, is independently H, —OH, F, Cl, Br, I, CN,C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀ alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₂alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4- to 12-membered heteroaryl, a 4-to 12-membered heterocyclyl, a 4- to 12-membered heteroaryl-C₁₋₁₀ alkyl,—CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴, —NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴,—(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂NR¹⁴R¹⁴,—NR¹⁴SO₂NR¹⁴R¹⁴, —CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴,—SO₂NR¹⁴COR¹⁴, —SO₂NR¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴,—NR¹⁴CONR¹⁴R¹⁴, —C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴, or —NR¹⁴COR¹⁴, or OR¹⁴,wherein the alkyl, cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl andheterocyclyl may be substituted with 0-2 R^(14a), and the heteroaryl andheterocyclyl consist of carbon atoms and 1, 2, 3, or 4 heteroatomsindependently selected from the group consisting of N, S, or O;

R¹⁴, at each occurrence, is independently selected from hydrogen, C₁₋₁₀alkyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, a 4- to 12-membered heteroaryl or a4- to 12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl may be substituted with 0-3 R^(14a) and theheteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO; or

alternatively, two R¹⁴'s are taken together with the atoms to which theyare attached to form a cyclic ring, wherein the cyclic ring may besubstituted with 0-1 R^(14a) and optionally contain 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO;

R^(14a), at each occurrence, is independently selected from F, Cl, Br,I, C₁₋₁₀ alkyl, haloC₁₋₁₀alkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, a 4- to12-membered heteroaryl, a 4- to 12-membered heterocyclyl, F, Cl, Br, I,—CN, —NO₂, —CO₂R₂₆, —CO₂NR₂₄R₂₄, —OCF₃, —OR₂₅, ═O, —CONR²⁴R²⁴, —COR²⁴,—SO₂R²⁴, —NR²⁴R²⁴, —NR²⁴CO₂R²⁴, —SO₂NR²⁴R²⁴, or C₆₋₁₀arylC₁₋₁₀alkyl,wherein the heteroaryl and heterocyclyl consist of carbon atoms and 1,2, 3, or 4 heteroatoms independently selected from the group consistingof N, S, or O;

R²⁴, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁵, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁶, at each occurrence, is independently selected from hydrogen,C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl;

m is 0 to 4;

n is 0 to 4; and

n−1 is 2 to 4.

In another aspect, the present invention provides compound of formula(Ia), wherein:

A is —(CH₂)_(m)—R²;

R¹ is

which may be substituted with 0-2 R¹³;

R² is phenyl, substituted with 0-2 R^(2a);

R^(2a), at each occurrence, is independently H, —OH, F, Cl, Br, I, orSO₂NH₂;

R³ is phenyl;

R¹³, at each occurrence, is independently H, —NR¹⁴SO₂R¹⁴, —CONR¹⁴R¹⁴,—SO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴, —SO₂NR¹⁴COR¹⁴, or OR—CO₂R¹⁴—;

R¹⁴, at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl;

R²⁴, at each occurrence, is independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁵, at each occurrence, is independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl;

R²⁶, at each occurrence, is independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl;

m is 0 to 4;

n is 0 to 4; and

n−1 is 2 to 4.

In another aspect, the present invention provides compound of formula(Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹ is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, or C₃₋₁₀cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R¹³; or

R is

any of which may be substituted with 0-2 R¹³

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹ is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, or C₃₋₁₀cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R¹³; or

R¹ is

any of which may be substituted with 0-2 R¹³.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹ is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, or C₃₋₁₀cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R¹³; or

R¹ is

any of which may be substituted with 0-2 R¹³.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹³, at each occurrence, is independently H, —OH, F, Cl, Br, I, C₁₋₆alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, a 4- to12-membered heteroaryl, wherein the heteroaryl is selected fromtetrazolyl, —CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴, —NR¹⁴SO₂R¹⁴, —CONR¹⁴R¹⁴,—(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR^(14b)R^(14b),—NR¹⁴COR¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, or —NR¹⁴R¹⁴, wherein the alkyl,cycloalkyl, phenyl, and heteroaryl may be substituted with 0-2 R^(14a),and the heteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3,or 4 heteroatoms independently selected from the group consisting of N,S, or O;

R¹⁴, at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, phenyl, wherein the alkyl, cycloalkyl, andphenyl, may be substituted with 0-3 R^(14a); or

alternatively, two R^(14b)'s are taken together with the atoms to whichthey are attached to form a cyclic ring, wherein the cyclic ring ismorpholinyl, piperidinyl, or piperazinyl, and may be substituted with0-1 C₁₋₆alkyl; and

R^(14a), at each occurrence, is independently selected from F, Cl, Br,I, C₁₋₆ alkyl, haloC₁₋₆alkyl, phenyl, or C₃₋₆cycloalkyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹³, at each occurrence, is independently H, C₁₋₆ alkyl, or a 4- to12-membered heteroaryl, wherein the heteroaryl is selected fromtetrazolyl, —CN, —NR¹⁴SO₂R¹⁴, —CONR¹⁴R¹⁴, —SO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴,—NR¹⁴CO₂NR^(14b)R^(14b), —NR¹⁴COR¹⁴, —CO₂R¹⁴, or —NR¹⁴R¹⁴, wherein thealkyl, and heteroaryl may be substituted with 0-2 R^(14a);

R¹⁴, at each occurrence, is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, or phenyl, wherein the alkyl, cycloalkyl, andphenyl, may be substituted with 0-3 R^(14a); or

two R^(14b)'s are taken together with the atoms to which they areattached to form a cyclic ring, wherein the cyclic ring is morpholinyl,and may be substituted with 0-1 C₁₋₆alkyl; and

R^(14a), at each occurrence, is independently selected from F, Cl, Br,I, C₁₋₆ alkyl, haloC₁₋₆alkyl, phenyl, or C₃₋₆cycloalkyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹³, at each occurrence, is independently H, —CN, —NHSO₂R¹⁴, —CONH₂,—SO₂NR¹⁴R¹⁴, —NHCO₂NR^(14b)R^(14b), —NHCOR¹⁴, or —NH₂; and

R¹⁴, at each occurrence, is independently selected from hydrogen, ormethyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R¹³, at each occurrence, is —SO₂NH₂.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

A is —(CH₂)_(m)—R², —CH(R²⁶)—R₂, —(CH₂)_(n-1)—O—R₂,—(CH₂)_(n-1)—NR²⁵—R₂, —CH(R²⁶)—CO₂—R², or —(CH₂)_(n-1)—NR²⁵—CO₂—R²;

R² is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, orpyridinone, any of which are substituted with 0-2 R^(2a); and

R^(2a), at each occurrence, is independently H, —OH, F, C₁₋₆ alkyl, C₁₋₆alkoxy, 6-SO₂NR¹⁴R¹⁴.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

A is —(CH₂)—R²;

R² is phenyl,

any of which are substituted with 0-1 R^(2a); and

R^(2a), at each occurrence, is independently H, —OH, F, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, or SO₂NR¹⁴R¹⁴.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

A is —(CH₂)—R²;

R² is phenyl,

any of which are substituted with 0-1 R^(2a); and

R^(2a), at each occurrence, is independently H, —OH, F, C₁₋₆ alkyl, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, or SO₂NR¹⁴R¹⁴.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

A is —(CH₂)—R²; and

R² is phenyl or

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

A is —(CH₂)—R²;

R² is phenyl, which is substituted with 0-1 R^(2a);

R^(2a), at each occurrence, is independently H or F;

R¹ is pyridinyl;

R³ is phenyl;

R^(3a) is halo;

R¹³, at each occurrence, is independently H, —NR¹⁴SO₂R¹⁴, —SO₂NR¹⁴R¹⁴,—NR¹⁴SO₂R¹⁴, —NR¹⁴COR¹⁴, —SO₂NR¹⁴COR¹⁴, or —CO₂R¹⁴; and

R¹⁴ is hydrogen or C₁₋₃alkyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R³ is phenyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

R²⁴, at each occurrence, is independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl; R²⁵, at each occurrence, isindependently selected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, orphenyl; and

R²⁶, at each occurrence, is independently selected from hydrogen,C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), wherein:

R²⁴, at each occurrence, is independently selected from hydrogen, methylor ethyl;

R²⁵, at each occurrence, is independently selected from hydrogen methylor ethyl; and

R²⁶, at each occurrence, is independently selected from hydrogen, methylor ethyl.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

m is 0-2; and

n−1 is 1-2.

In another aspect, the present invention provides compound of formula(I) or (Ia), or enantiomers, diastereomers, tautomers, prodrugs or saltsthereof wherein:

m is 1 or 2;

n−1 is 2; and

n is 1.

In another embodiment, compounds, enantiomers, diastereomers, tautomers,or salt thereof, of the present invention are selected from thecompounds exemplified in the examples.

In one embodiment, pharmaceutical compositions comprising atherapeutically effective amount of at least one compound of formula(I), (Ia), and/or compounds exemplified in the examples.

In another embodiment, pharmaceutical compositions comprising atherapeutically effective amount of at least one compound of formula(I), (Ia), and/or compounds exemplified in the examples, and at leastone other therapeutic agent, for example, anti-arrhythmic agents,calcium channel blockers, anti-platelet agents, anti-hypertensiveagents, anti thrombotic/anti thrombolytic agents, anti coagulants,HMG-CoA reductase inhibitors, anti diabetic agents, thyroid mimetics,mineralocorticoid receptor antagonists, and cardiac glycosides, areprovided.

In yet another embodiment, pharmaceutical compositions comprising atherapeutically effective amount of at least one compound of formula(I), (Ia), or compounds exemplified in the examples, and at least oneother therapeutic agent, for example, sotalol, dofetilide, diltiazem,verapamil, clopidogrel, cangrelor, ticlopidine, CS-747, ifetroban,aspirin, a beta adrenergic blocker, an ACE inhibitor, an A IIantagonist, an ET antagonist, a dual ET/A II antagonist, a vasopepsidaseinhibitor, tPA, recombinant tPA, TNK, nPA, a factor VIIa inhibitor, afactor Xa inhibitor, a factor XIa inhibitor, a thrombin inhibitor,warfarin, a heparin, pravastatin, lovastatin, atorvastatin, simvastatin,NK-104, ZD-4522, a biguanide, a biguanide/glyburide combination,spironolactone, eplerinone, digitalis and ouabain, are provided.

In still yet another embodiment, pharmaceutical compositions comprisinga therapeutically effective amount of at least one compound of formula(I), (Ia), or compounds exemplified in the examples, and at least oneother therapeutic agent, for example, captopril, zofenopril, fosinopril,enalapril, ceranopril, cilazopril, delapril, pentopril, quinapril,ramipril, lisinopril, omapatrilat, gemopatrilat, and apixaban, areprovided.

In one embodiment, methods of treating or preventing arrhythmiacomprising administering to a patient in need thereof an effectiveamount of at least one compound of formula (I), (Ia), or compoundsexemplified in the examples, are provided.

In another embodiment, methods of treating or preventingsupraventricular arrhythmia, for example, atrial fibrillation and atrialflutter, comprising administering to a patient in need thereof aneffective amount of at least one compound of formula (I), (Ia), orcompounds exemplified in the examples, are provided.

In one embodiment, a method of controlling heart rate comprisingadministering to a patient in need thereof an effective amount of atleast one compound of formula (I), (Ia), or compounds exemplified in theexamples, is provided.

In another embodiment, methods of treating an I_(Kur)-associatedconditions, for example, gastrointestinal disorders, such as refluxesophagitis and a motility disorder; inflammatory and/or immunologicaldiseases, such as chronic obstructive pulmonary disease; diabetes;cognitive disorders; migraines; epilepsy; and hypertension, comprisingadministering to a patient in need thereof an effective amount of atleast one compound of formula (I), (Ia), or compounds exemplified in theexamples, are provided.

Another aspect of this invention is directed to a composition comprisinga compound of the invention together with a pharmaceutically acceptablecarrier, diluent, or excipient. When water is a carrier or diluent, thecomposition optionally further comprises another pharmaceuticallyacceptable carrier or diluent and/or a pharmaceutically acceptableexcipient. Within this aspect are such compositions for pharmaceuticaluse.

Another aspect of this invention is directed to a composition comprisinga compound of the invention together with a pharmaceutically acceptablecarrier, diluent, or excipient. When water is a carrier or diluent, thecomposition optionally further comprises another pharmaceuticallyacceptable carrier or diluent and/or a pharmaceutically acceptableexcipient. Within this aspect are such compositions for pharmaceuticaluse.

Another aspect of this invention is directed to treatment of diseases ordisorders associated with inhibition of potassium channel function,wherein the disease or disorder is atrial fibrillation, controllingheart rate, and/or prophylactically treating arrhythmia, comprisingadministering a therapeutically effective amount of a compound of thepresent invention or an individual isomer or mixture of isomers or apharmaceutically acceptable salt thereof.

The compounds of the invention may be useful in therapy.

The compounds of the invention may be used for the manufacture of amedicament for the treatment and/or prophylaxis of diseases or disordersassociated with inhibition of potassium channel function, of the K_(v)1subfamily of voltage gated K⁺ channels, of K_(v)1.5 (which have beenlinked to the ultra-rapidly activating delayed rectifier K⁺ currentI_(Kur), and/or K_(v)1.3 channels, and/or K_(v)1.1 channels.

The compounds of the invention can be used alone, in combination withother compounds of the present invention, or in combination with one ormore, preferably one to two other agent(s).

The invention may be embodied in other specific forms without departingfrom the spirit or essential attributes thereof. This invention alsoencompasses all combinations of alternative aspects of the inventionnoted herein. It is understood that any and all embodiments of thepresent invention may be taken in conjunction with any other embodimentto describe additional embodiments of the present invention.Furthermore, any elements of an embodiment may be combined with any andall other elements from any of the embodiments to describe additionalembodiments.

Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solvent orsolvent mixture appropriate to the reagents and materials employed andsuitable for the transformations being effected. It will be understoodby those skilled in the art of organic synthesis that the functionalitypresent on the molecule should be consistent with the transformationsproposed. This will sometimes require a judgment to modify the order ofthe synthetic steps or to select one particular process scheme overanother in order to obtain a desired compound of the invention.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

The compounds of the present invention may be prepared by the exemplaryprocesses described in the following schemes and working examples, aswell as relevant published literature procedures that are used by oneskilled in the art. Exemplary reagents and procedures for thesereactions appear hereinafter and in the working examples. Protection andde-protection of functional groups in the processes below may be carriedout by procedures generally known in the art (see, for example, Greene,T. W. et al., Protecting Groups in Organic Synthesis, Third Edition,Wiley (1999). General methods of organic synthesis and functional grouptransformations are found in: Trost, B. M. et al., eds., ComprehensiveOrganic Synthesis: Selectivity, Strategy & Efficiency in Modern OrganicChemistry, Pergamon Press, New York, N.Y. (1991); March, J., AdvancedOrganic Chemistry: Reactions, Mechanisms, and Structure, Fourth Edition,Wiley & Sons, New York, N.Y. (1992); Katritzky, A. R. et al., eds.,Comprehensive Organic Functional Groups Transformations, First Edition,Elsevier Science Inc., Tarrytown, N.Y. (1995); Larock, R. C.,Comprehensive Organic Transformations, VCH Publishers, Inc., New York,N.Y. (1989); and references therein.

ABBREVIATIONS

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “° C.” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar, “nM”for nanomolar, “mol” for mole or moles, “mmol” for millimole ormillimoles, “min” for minute or minutes, “h” for hour or hours, “rt” forroom temperature, “Rt” for retention time, “atm” for atmosphere, “psi”for pounds per square inch, “conc.” for concentrate, “sat” or “sat'd”for saturated, “MW” for molecular weight, “mp” for melting point, “MS”or “Mass Spec” for mass spectrometry, “ESI” for electrospray ionizationmass spectroscopy, “HR” for high resolution, “HRMS” for high resolutionmass spectrometry, “LCMS” for liquid chromatography mass spectrometry,“HPLC” for high pressure liquid chromatography, “RP HPLC” for reversephase HPLC, “TLC” or “tlc” for thin layer chromatography, “NMR” fornuclear magnetic resonance spectroscopy, “nOe” for nuclear Overhausereffect spectroscopy, “¹H” for proton, “δ” for delta, “s” for singlet,“d” for doublet, “t” for triplet, “q” for quartet, “m” for multiplet,“br” for broad, “Hz” for hertz, and “α”, “β”, “R”, “S”, “E”, and “Z” arestereochemical designations familiar to one skilled in the art.

Solvents, temperatures, pressures, and other reaction conditions mayreadily be selected by one of ordinary skill in the art. Startingmaterials are commercially available or can be readily prepared by oneof ordinary skill in the art using known methods. For all of the schemesand compounds described below X¹, X², A and R¹ are as described for acompound of Formula (I). The following are the definitions of symbolsused in Scheme 1 and the Examples:

AcOH Acetic acid

Ar Aryl

t-BuOK Potassium tert-butoxide

CH₂Cl₂ Dichloromethane CH₃CN Acetonitrile CDCl₃ Deutero-chloroform CHCl₃Chloroform

Cs₂CO₃ Cesium carbonate

DCM Dichloromethane DIPEA Diisopropylethylamine

DMF N,N-dimethyl formamideEtOAc Ethyl acetate

Et Ethyl

HCOOH Formic acidHCl Hydrochloric acidK₂CO₃ Potassium carbonate

Me Methyl MeOH Methanol

MTBE Methyl tert-butyletherNaCl Sodium chlorideNaH Sodium hydrideNaHCO₃ Sodium bicarbonateNaOH Sodium hydroxideNaOMe Sodium methoxideNa₂SO₄ Sodium sulfateNCS N-Chloro succinamide

NH₂Cl Monochloroamine

NH₄COOH Ammonium formateNH₄HCO₃ Ammonium bicarbonateNH₄OAc Ammonium acetatePd(OAc)₂ Palladium(II) acetatePd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium (0)

Pd(TPP)₄ Tetrakis(triphenylphosphine)palladium (0)

Pd(TPP)₂Cl₂ Bis(diphenylphosphine) palladium(II) dichloridePOCl₃ Phosphorus oxychlorideTFA Trifluoroacetic acid

THF Tetrahydrofuran

A particularly useful compendium of synthetic methods which may beapplicable to the preparation of compounds of the present invention maybe found in Larock, R. C., Comprehensive Organic Transformations, VCH,New York (1989). Preferred methods include, but are not limited to,those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

The novel compounds of this invention may be prepared using thereactions and techniques described in this section. Also, in thedescription of the synthetic methods described below, it is to beunderstood that all proposed reaction conditions, including choice ofsolvent, reaction atmosphere, reaction temperature, duration of theexperiment and workup procedures, are chosen to be the conditionsstandard for that reaction, which should be readily recognized by oneskilled in the art. Restrictions to the substituents that are compatiblewith the reaction conditions will be readily apparent to one skilled inthe art and alternate methods must then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene et al. (Protective Groups in Organic Synthesis,Wiley and Sons (1991)).

Compounds of general formula (I) can be synthesized by the generalsequence shown in Scheme 1. Commercially available5-methyl-3,4-dihydro-2H-pyrrole 1 was treated with N-chlorosuccinimidefollowed by sodium methoxide to generate chloro pyrrole ester 2.Compound 2 was converted to methyl1-amino-3-chloro-1H-pyrrole-2-carboxylate (3) utilizing aminatingreagents such as monochloramine and 3 was subsequently acylated to yieldβ-ketoester intermediate 4. Compound 4 was treated with a base, forexample potassium tertiary butoxide in solvent such as THF to yieldethyl5-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxylate5. Compound 5 was treated with base such as NaOH to hydrolyze the esterand affect decarboxylation of the intermediate acid to obtain compound6. Compound 6 was converted to derivative 7 on treatment withchlorinating agents, for example, POCl₃. Subsequent displacement of theC4 chloro with an amine gave intermediate 8 regioselectively. Usingdifferent palladium reagent/ligand combinations we could achieveregioselective Suzuki cross couplings at C2 and C5 to arrive atcompounds of general formula (I).

EXAMPLES

The following Examples are offered to better illustrate, but not limit,some of the preferred embodiments of the application and are not meantto be limiting of the scope of the invention. Abbreviations and chemicalsymbols have their usual and customary meanings unless otherwiseindicated. Unless otherwise indicated, the compounds described hereinhave been prepared, isolated and characterized using the schemes andother methods disclosed herein or may be prepared using the same.

General Methods

The following methods were used in the working Examples, except wherenoted otherwise.

Analytical HPLC and HPLC/MS Methods Employed in Characterization ofExamples

Reverse phase analytical HPLC/MS was performed on Shimadzu LC10ASsystems coupled with Waters ZMD Mass Spectrometers or Waters AQUITY®system coupled with a Waters MICROMASS® ZQ Mass Spectrometer. Chiralanalytical LC was performed on a Berger Analytical SFC instrument.

Condition 1: Column=Ascentis Express C18, 2.1×50 mm, 2.7 μm SolventA=CH₃CN (2%)+10 mM NH₄COOH in H₂O (98%) Solvent B=CH₃CN (98%)+10 mMNH₄COOH in H₂O (2%) Start % B=0; Final % B=100

Gradient time=1.4 min; Stop time=4 minIsocratic time=1.6 minFlow Rate=1 mL/min; Wavelength=220 nm

Condition 2: Column=XBridge C18, 2.1×50 mm, 2.5 μm Solvent A=CH₃CN(5%)+10 mM NH₄HCO₃ in H₂O (95%) Solvent B=CH₃CN (95%)+10 mM NH₄HCO₃ inH₂O (5%) Start % B=0; Final % B=100

Gradient time=1.7 min; Stop time=4 minIsocratic time=1.5 minFlow Rate=1 mL/min; Wavelength=220 nm

Condition 3: Column=ZORBAX® SB C18, 4.6×50 mm, 3.5 μm Solvent A=CH₃CN(10%)+20 mM NH₄OAc in H₂O (90%) Solvent B=CH₃CN (90%)+20 mM NH₄OAc inH₂O (10%) Start % B=0; Final % B=100

Gradient time=2.5 min; Stop time=3 minFlow Rate=2.5 mL/min; Wavelength=220 nm

Condition 4: Column=XBridge BEH C18, 2.1×50 mm, 2.5 m Solvent A=0.1%HCOOH in H₂O Solvent B=0.07% HCOOH in CH₃CN Start % B=10; Final % B=100

Gradient time=2.0 min; Stop time=4.0 minIsocratic time=1. minFlow Rate=1.2 mL/min; Wavelength=220 nm

Condition 5: Column=Acquity BEH C18, 2.1×50 mm, 1.7 μm Solvent A=Buffer:CH₃CN (95:5) Solvent B=Buffer: CH₃CN (5:95)

Buffer=10 mM NH₄OAc in H₂O (pH 5, adjusted with HCOOH)

Start % B=5; Final % B=95

Gradient time=1.1 min; Stop time=2.4 minIsocratic time=0.6 minFlow Rate=0.8 mL/min; Wave length=220 nm

Condition 6: Column: Acquity BEH C18, 2.1×50 mm, 1.7 μm Solvent A=0.1%TFA in H₂O Solvent B=0.1% TFA in CH₃CN Start % B=2; Final % B=98

Gradient time=1 min; Stop time=2.2 minIsocratic time=0.6 minFlow Rate=0.8 mL/min; Wave length=220 nm

Condition 7: Column=XBridge BEH C18, 2.1×50 mm, 2.5 μm Solvent A=1%HCOOH in H₂O Solvent B=CH₃CN Start % B=5; Final % B=100

Gradient time=2.5 min; Stop time=4 minFlow=1 mL/min; Wave length=220 nm

Condition 8: Column=Inertsil 3 V ODS C18, 20×250 mm, 5 μm Solvent A=10mM NH₄OAc in H₂O Solvent B=CH₃CN Start % B=70; Final % B=90

Gradient time=16 min; Stop time=30 minIsocratic time=9 minFlow Rate=16 mL/min; Wave length=220 nm

Condition 9: Column=PHENOMENEX® C18, 19×250 mm, 5 μm

Solvent A=10 mM NH₄OAc in H₂O (pH 4.5, adjusted with AcOH)

Solvent B=CH₃CN Start % B=6; Final % B=60

Gradient time=20 min; Stop time=35 minFlow=16 mL/min; Wave length=220 nm

Condition 10: Column=SunFire C18, 20×250 mm, 5 μm

Solvent A=10 mM NH₄OAc in H₂O (pH 4.5, adjusted with AcOH)

Solvent B=CH₃CN Start % B=50; Final % B=90

Gradient time=10 min; Stop time=20 minIsocratic time=5 minFlow=16 mL/min; Wave length=220 nm

Condition 11: Column=YMC C18, 150×20 mm, 5 μm

Solvent A=10 mM NH₄OAc in H₂O (pH 4.6, adjusted with AcOH)

Solvent B=CH₃CN Start % B=30; Final % B=70

Gradient time-1=10 min;

Start % B=70; Final % B=100

Gradient time-2=7.1 min; Stop time=20 minIsocratic time=5 minFlow=15 mL/min; Wave length=220 nm

Condition 12: Column=SYMMETRY® C18, 21.2×250 mm, 7 μm

Solvent A=10 mM NH₄OAc in H₂O (pH 4.5, adjusted with AcOH)

Solvent B=CH₃CN Start % B=30; Final % B=65

Gradient time=5 min; Stop time=25 minFlow=16 mL/min; Wave length=220 nm

Condition 13: Column=Luna C18, 19×250 mm, 7 μm Solvent A=10 mM NH₄OAc inH₂O Solvent B=CH₃CN Start % B=30; Final % B=100

Gradient time=8 min; Stop time=20 minIsocratic time=7 minFlow=16 mL/min; Wave length=220 nm

Condition 14: Column=XBridge Phenyl, 4.6×150 mm, 3.5 m Solvent A=Buffer:CH₃CN (95:5) Solvent B=Buffer: CH₃CN (5:95)

Buffer=0.05% TFA in H₂O (pH 2.5, adjusted with dilute ammonia)

Start % B=10; Final % B=100

Gradient time=12 min; Stop time=23 minIsocratic time=3 minFlow Rate=1 mL/min; Wavelength=220 and 254 nm

Condition 15: Column=SunFire C18, 4.6×150 mm, 3.5 μm Solvent A=Buffer:CH₃CN (95:5) Solvent B=Buffer: CH₃CN (5:95)

Buffer=0.05% TFA in H₂O (pH 2.5, adjusted with dilute ammonia)

Start % B=10; Final % B=100

Gradient time=12 min; Stop time=23 minIsocratic time=3 minFlow Rate=1 mL/min; Wavelength=220 and 254 nm

NMR Employed in Characterization of Examples

¹H NMR spectra were obtained with Bruker or JEOL® Fourier transformspectrometers operating at frequencies as follows: ¹H NMR: 400 MHz or300 MHz (Bruker) ¹³C NMR: 100 MHz or 75 MHz (Bruker). Spectra data arereported in the format: chemical shift (multiplicity, couplingconstants, number of hydrogens). Chemical shifts are specified in ppmdownfield of a tetramethylsilane internal standard (6 units,tetramethylsilane=0 ppm) and/or referenced to solvent peaks, which in ¹HNMR spectra appear at 2.49 ppm for CD₂HSOCD₃, 3.30 ppm for CD₂HOD, and7.24 ppm for CHCl₃, and which in ¹³C NMR spectra appear at 39.7 ppm forCD₃SOCD₃, 49.0 ppm for CD₃OD, and 77.0 ppm for CDCl₃. All ¹³C NMRspectra were proton decoupled.

Example 15-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridine-3-sulfonamide

The commercially available methyl 3-chloro-1H-pyrrole-2-carboxylate(1.50 g, 94.0%, yellow solid) was synthesized according to Fang et al.,J. Med. Chem., 53:7967-7978 (2010) using 2-methyl-1-pyrroline (0.831 g,10.0 mmol, commercial), NCS (10.7 g, 80.0 mmol) and NaOMe in MeOH (3M,20 mL, 60.0 mmol). LCMS (Condition 6): retention time 1.71 min,[M+1]=160.10. ¹H NMR (400 MHz, CDCl₃) δ 3.90 (s, 3H), 6.25 (t, J=3.0 Hz,1H), 6.86 (t, J=3.0 Hz, 1H), 9.17 (br s, 1H).

Synthesis of Monochloramine Reagent

Ammonium chloride (3.00 g, 60.0 mmol) was dissolved in ether (110 mL)and the solution cooled to −5° C. Concentrated ammonium hydroxide (28 M,4.70 mL, 120 mmol) was added dropwise. Commercial bleach that is sodiumhypochorite (2M, 72.0 mL, 0.144 mol) was added via addition funnel over15 min. The reaction mixture was stirred for 15 min, the layers wereseparated and the organic layer was washed with brine. The organic layerwas dried over powdered CaCl₂ in a freezer for 1 h and stored at −40° C.The approximate concentration of monochloramine is 0.15 M.

To a stirred solution of methyl 3-chloro-1H-pyrrole-2-carboxylate (1.00g, 6.30 mmol) in DMF (15 mL) was added NaH (0.45 g, 18.80 mmol, 99%,dry) and the contents were stirred for 1 h at ambient temperature. NH₂Cl(42.0 mL, 0.327 g, 6.30 mmol) was added at −10° C. to the reactionmixture and the contents were stirred for another 30 min at −10° C. Thesolvents were removed under reduced pressure and the residue wasextracted with MTBE. The MTBE layer was passed through anhydrous Na₂SO₄and concentrated under reduced pressure to give a brown solid. The cruderesidue was purified by combiflash (REDISEP®, silica gel, 40 g, 20%EtOAc/hexanes) to give a methyl1-amino-3-chloro-1H-pyrrole-2-carboxylate (0.750 g, 69.0%) as a yellowsolid. LCMS (Condition 3): retention time 0.68 min, [M+1]=175.1. ¹H NMR(400 MHz, DMSO-d₆) δ 3.80 (s, 3H), 6.11 (d, J=2.8 Hz, 1H), 6.28 (s, 2H),7.06 (d, J=2.8 Hz, 1H).

To a stirred solution of methyl1-amino-3-chloro-1H-pyrrole-2-carboxylate (3.80 g, 21.7 mmol) in CH₂Cl₂(50 mL) was added pyridine (5.28 mL, 65.3 mmol). The resulting mixturewas cooled to 0° C. and ethyl malonyl monochloride (3.28 g, 21.7 mmol)was added dropwise. The reaction mixture was stirred at 0° C. for 5 min.The reaction mixture was quenched by the addition of water. The organiclayer was separated and the aqueous layer was extracted with DCM. Thecombined organic extracts were dried over anhydrous Na₂SO₄, filtered,and concentrated under reduced pressure. The resulting residue waspurified by combiflash (REDISEP®, silica gel, 40 g, 30% EtOAc/hexanes)to afford methyl3-chloro-1-(3-ethoxy-3-oxopropanamido)-1H-pyrrole-2-carboxylate (2.85 g,43.1%) as a yellow oil. LCMS (Condition 7): retention time 1.79 min,[M+1]=289.0. ¹H NMR (400 MHz, DMSO-d₆) δ 1.21 (t, J=7.2 Hz, 3H), 3.41(s, 2H), 3.76 (s, 3H), 4.13 (q, J=7.2 Hz, 2H), 6.32 (d, J=2.8 Hz, 1H),7.14 (d, J=2.8 Hz, 1H), 11.53 (s, 1H).

To a solution of methyl3-chloro-1-(3-ethoxy-3-oxopropanamido)-1H-pyrrole-2-carboxylate (2.85 g,9.87 mmol) in THF (50 mL) was added t-BuOK (3.32 g, 29.6 mmol) at roomtemperature and stirred for 1 h. The reaction mixture was quenched bythe addition of water and neutralized by the addition of aqueous citricacid solution. The reaction mixture was extracted with EtOAc (2×50 mL).The combined organic extracts were washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresulting residue was purified by combiflash (REDISEP®, silica gel, 40g, 40% EtOAc/hexanes) to afford ethyl5-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxylate(1.70 g, 67.1%) as a yellow solid. LCMS (Condition 1): retention time1.36 min, [M+1]=256.6. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32 (t, J=7.2 Hz,3H), 4.35 (q, J=7.2 Hz, 2H), 6.68 (d, J=2.8 Hz, 1H), 7.59 (d, J=2.8 Hz,1H), 11.51 (br s, 1H).

To a stirred solution of ethyl5-chloro-2,4-dioxo-1,2,3,4-tetrahydropyrrolo[1,2-b]pyridazine-3-carboxylate(1.70 g, 6.62 mmol) in 1,4-dioxane (15 mL) was added NaOH (2.65 g, 66.2mmol) in water (3 mL). The resulting suspension was heated in a sealedtube at 140° C. for 2 h. The reaction mixture was allowed to cool toambient temperature and water was added to the reaction mixture. Thereaction mixture was acidified by the addition of 1.5N aq.HCl solutionand extracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The resulting residue was purified by combiflash(REDISEP®, silica gel, 12 g, 50% EtOAc/hexanes) to obtain5-chloropyrrolo[1,2-b]pyridazine-2,4-diol (1.00 g, 79.0%) as anoff-white solid. LCMS (Condition 7): retention time 1.81 min,[M+1]=185.0. ¹H NMR (400 MHz, DMSO-d₆) δ 5.61 (s, 1H), 6.48 (d, J=2.8Hz, 1H), 7.38 (d, J=2.8 Hz, 1H), 10.76 (br s, 1H), 11.50 (s, 1H).

To a stirred suspension of 5-chloropyrrolo[1,2-b]pyridazine-2,4-diol(1.00 g, 5.42 mmol) in toluene (5 mL) was added DIPEA (1.89 mL, 10.8mmol) followed by POCl₃ (2.02 mL, 21.6 mmol). The resulting solution washeated in a sealed tube at 125° C. for 16 h. The reaction mixture wasallowed to cool to room temperature and the volatile components wereevaporated under reduced pressure. The resulting residue was azeotropedwith toluene three times and the residue was purified by combiflash(REDISEP®, silica gel, 12 g, 2% EtOAc/hexanes) to obtain2,4,5-trichloropyrrolo[1,2-b]pyridazine (140 mg, 11.6%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (d, J=3.2 Hz, 1H), 7.23 (s, 1H),8.07 (d, J=3.2 Hz, 1H).

2,4,5-Trichloropyrrolo[1,2-b]pyridazine (140 mg, 0.632 mmol) inbenzylamine (0.800 mL, 7.32 mmol) was irradiated in microwave at 100° C.for 1.5 h. The reaction mixture was allowed to cool to ambienttemperature and the volatile components were evaporated under reducedpressure. The resulting residue was purified by combiflash (REDISEP®,silica gel, 12 g, 5% EtOAc/hexanes) to obtainN-benzyl-2,5-dichloropyrrolo[1,2-b]pyridazin-4-amine (135 mg, 71.6%) asa white solid. LCMS (Condition 1): retention time 2.15 min, [M+1]=291.6.¹H NMR (400 MHz, DMSO-d₆) δ 4.60 (d, J=6.4 Hz, 2H), 5.69 (s, 1H), 6.71(d, J=2.8 Hz, 1H), 7.26-7.28 (m, 1H), 7.37-7.40 (m, 5H), 7.64 (d, J=2.8Hz, 1H).

To a stirred solution ofN-benzyl-2,5-dichloropyrrolo[1,2-b]pyridazin-4-amine (135 mg, 0.462mmol) andN-(tert-butyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-3-sulfonamide(314 mg, 0.924 mmol) (Johnson et al., WO 2011/28741) in 1,4-dioxane (6mL) and water (1 mL) was added Pd(TPP)₄ (53.4 mg, 0.0460 mmol) followedby Cs₂CO₃ (452 mg, 1.39 mmol). The resulting suspension was purged withnitrogen for 5 min. The reaction mixture was heated in a sealed tube at100° C. for 16 h. The reaction mixture was allowed to cool to roomtemperature and diluted with water. The reaction mixture was thenextracted with EtOAc. The combined organic extracts were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by combiflash (REDISEP®,silica gel, 12 g, 30% EtOAc/hexanes) and the resulting product wasfurther purified by preparative TLC (silica gel, 30% EtOAc/hexanes) toafford5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamide(115 mg, 47.1%) as a yellow solid. LCMS (Condition 1): retention time2.33 min, [M+1]=470.0. ¹H NMR (400 MHz, DMSO-d₆) δ 1.13 (s, 9H), 4.73(d, J=6.4 Hz, 2H), 6.29 (s, 1H), 6.78 (d, J=2.8 Hz, 1H), 7.25-7.27 (m,2H), 7.34-7.38 (m, 2H), 7.46-7.48 (m, 2H), 7.78 (d, J=2.8 Hz, 1H), 7.88(s, 1H), 8.63 (t, J=2.0 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H), 9.22 (d, J=2.0Hz, 1H).

To a stirred solution of5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamide(50.0 mg, 0.106 mmol) and phenylboronic acid (15.6 mg, 0.128 mmol) in1,4-dioxane (2 mL) and water (0.4 mL) was added2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10.1 mg, 0.0210mmol), Pd(OAc)₂ (2.38 mg, 0.0106 mmol) followed by K₂CO₃ (44.1 mg, 0.319mmol). The resulting suspension was purged with nitrogen for 5 minutes.The reaction mixture was heated in a sealed tube at 100° C. for 2 h. Thereaction mixture was allowed to cool to ambient temperature and dilutedwith water. The reaction mixture was extracted with EtOAc (2×10 mL). Thecombined organic extracts were washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by preparative TLC (silica gel, 40% EtOAc/hexanes)to afford5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamide(30.0 mg, 54.0%) as a yellow solid. LCMS (Condition 1): retention time2.33 min, [M+1]=512.2. HPLC (Condition 15): retention time=24.50 min,purity 99.70%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.15 (s, 9H), 4.58 (d, J=5.2Hz, 2H), 5.58 (dd, J=5.2 Hz, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.77 (d, J=2.8Hz, 1H), 7.26-7.36 (m, 6H), 7.39-7.43 (m, 2H), 7.48-7.51 (m, 2H), 7.87(d, J=2.8 Hz, 1H), 7.91 (s, 1H), 8.73 (t, J=2.0 Hz, 1H), 9.04 (d, J=2.0Hz, 1H), 9.35 (d, J=2.0 Hz, 1H).

To a solution of5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamide(35.0 mg, 0.0680 mmol) in acetonitrile (2 mL) was added triflic acid(0.300 mL, 3.38 mmol) at room temperature and stirred for 30 min. The 10reaction mixture was quenched by the addition of 10% NaHCO₃ solution (5mL) and extracted with EtOAc (2×20 mL). The combined organic extractswere washed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The resulting residue was purifiedby preparative HPLC (Condition 9 as described in general methods) toyield5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridine-3-sulfonamide(21.0 mg, 66.7%) as a yellow solid. LCMS (Condition 1): retention time2.10 min, [M+1]=456.0. HPLC (Condition 15): retention time 10.85 min,purity 99.93%. ¹H NMR (400 MHz, DMSO-d₆) δ 4.59 (d, J=5.2 Hz, 2H), 5.56(t, J=5.2 Hz, 1H), 6.49 (s, 1H), 6.78 (d, J=2.8 Hz, 1H), 7.25-7.52 (m,11H), 7.88 (d, J=2.8 Hz, 1H), 8.76 (dd, J=2.0 Hz, J=2.4 Hz, 1H), 9.05(d, J=2.4 Hz, 1H), 9.37 (d, J=2.0 Hz, 1H).

Example 2N-((5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)sulfonyl)acetamide

To a suspension of5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridine-3-sulfonamide(15.0 mg, 0.0330 mmol) in CH₂Cl₂ (2 mL) was added triethylamine (0.0140mL, 0.0990 mmol) followed by acetyl chloride (0.00351 mL, 0.0490 mmol).The reaction mixture was stirred at ambient temperature for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith CH₂Cl₂ (2×10 mL). The combined extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The resultingresidue was purified by preparative HPLC (Condition 10 as described ingeneral methods) to affordN-((5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)sulfonyl)acetamide(8.00 mg, 47.9%) as a yellow solid. LCMS (Condition 2): retention time1.89 min, [M+1]=497.6. HPLC (Condition 15): retention time 20.82 min,purity 98.40%. ¹H NMR (400 MHz, DMSO-d₆) δ 1.85 (s, 3H), 4.58 (d, J=5.2Hz, 2H), 5.57 (dd, J=5.2 Hz, J=5.6 Hz, 1H), 6.46 (s, 1H), 6.77 (d, J=2.8Hz, 1H), 7.25-7.51 (m, 11H), 7.90 (d, J=2.8 Hz, 1H), 8.72 (br s, 1H),9.02 (d, J=2.0 Hz, 1H), 9.32 (br s, 1H).

Example 3N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)acetamide

2-(5-Aminopyridin-3-yl)-N-benzyl-5-chloropyrrolo[1,2-b]pyridazin-4-amine(100 mg, 47.3%, off-white solid) was prepared fromN-benzyl-2,5-dichloropyrrolo[1,2-b]pyridazin-4-amine (150 mg, 0.513mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine(226 mg, 1.03 mmol, commercial), Pd(TPP)₄ (59.3 mg, 0.0510 mmol) andCs₂CO₃ (502 mg, 1.54 mmol) by the methods described for the preparationof5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamidein Example 1. The residue was purified by combiflash (REDISEP®, silicagel, 12 g, 2% MeOH/DCM) and the resulting product was further purifiedby washing with diethyl ether. LCMS (Condition 4): retention time 2.00min, [M+1]=350.0. ¹H NMR (400 MHz, DMSO-d₆) δ 4.67 (d, J=6.0 Hz, 2H),5.45 (br s, 2H), 6.04 (s, 1H), 6.71 (d, J=3.2 Hz, 1H), 7.13 (t, J=6.0Hz, 1H), 7.25-7.28 (m, 1H), 7.35-7.45 (m, 5H), 7.67 (d, J=3.2 Hz, 1H),7.97 (d, J=2.4 Hz, 1H), 8.11 (d, J=2.0 Hz, 1H).

N-(5-(4-(Benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)acetamide(30.0 mg, 53.0%, yellow solid) was prepared from2-(5-aminopyridin-3-yl)-N-benzyl-5-chloropyrrolo[1,2-b]pyridazin-4-amine(50.0 mg, 0.143 mmol), triethylamine (0.0600 mL, 0.429 mmol) and acetylchloride (0.0120 mL, 0.172 mmol) by the methods described for thepreparation ofN-((5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)sulfonyl)acetamidein Example 2. The residue was purified by preparative TLC (silica gel,5% MeOH/DCM). LCMS (Condition 4): retention time 2.48 min, [M+1]=392.0.¹H NMR (400 MHz, DMSO-d₆) δ 3.04 (s, 3H), 4.69 (d, J=6.0 Hz, 2H), 6.13(s, 1H), 6.74 (d, J=2.8 Hz, 1H), 7.23-7.27 (m, 2H), 7.34-7.38 (m, 2H),7.45-7.47 (m, 2H), 7.72 (d, J=2.8 Hz, 1H), 7.99 (dd, J=1.6 Hz, J=2.4 Hz,1H), 8.44 (d, J=2.4 Hz, 1H), 8.68 (d, J=1.6 Hz, 1H), 9.92 (br s, 1H).

N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)acetamide(25.0 mg, 40.7%, yellow solid) was prepared fromN-(5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)acetamide(55.0 mg, 0.140 mmol) and phenylboronic acid (20.5 mg, 0.168 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (13.4 mg, 0.0280mmol), Pd(OAc)₂ (3.15 mg, 14.0 mol) and K₂CO₃ (58.2 mg, 0.421 mmol) bythe methods described for the preparation of5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamidein Example 1. The residue was purified by combiflash (REDISEP®, silicagel, 12 g, 15% EtOAc/hexanes) and the resulting product was furtherpurified by preparative HPLC (Condition 10 as described in generalmethods). LCMS (Condition 4): retention time 2.55 min, [M+1]=434.2. HPLC(Condition 15): retention time 14.91 min, purity 99.16%. ¹H NMR (300MHz, DMSO-d₆) δ 2.12 (s, 3H), 4.54 (d, J=5.4 Hz, 2H), 5.53 (dd, J=5.1Hz, J=5.4 Hz, 1H), 6.31 (s, 1H), 6.74 (d, J=2.7 Hz, 1H), 7.23-7.52 (m,10H), 7.81 (d, J=2.7 Hz, 1H), 8.56 (dd, J=2.1 Hz, J=2.4 Hz, 1H), 8.78(d, J=2.1 Hz, 1H), 8.83 (d, J=2.4 Hz, 1H), 10.31 (s, 1H).

Example 4N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)methanesulfonamide

To a stirred solution of2-(5-aminopyridin-3-yl)-N-benzyl-5-chloropyrrolo[1,2-b]pyridazin-4-amine(75.0 mg, 0.214 mmol) in THF (3 mL) was added triethylamine (0.179 mL,1.29 mmol) followed by methanesulfonyl chloride (25.0 μL, 0.322 mmol).The resulting solution was stirred at room temperature for 12 h. Thereaction mixture was quenched by the addition of water and extractedwith CH₂Cl₂. The combined organic extracts were dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas purified by preparative HPLC (Condition 12 as described in generalmethods) to affordN-(5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)methanesulfonamide(37.5 mg, 40.0%) as a yellow solid. LCMS (Condition 1): retention time2.05 min, [M+1]=427.6. ¹H NMR (400 MHz, DMSO-d₆) δ 3.04 (s, 3H), 4.69(d, J=6.0 Hz, 2H), 6.13 (s, 1H), 6.74 (d, J=2.8 Hz, 1H), 7.23-7.27 (m,2H), 7.34-7.38 (m, 2H), 7.45-7.47 (m, 2H), 7.72 (d, J=2.8 Hz, 1H), 7.99(dd, J=1.6 Hz, J=2.4 Hz, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.68 (d, J=1.6 Hz,1H), 9.92 (br s, 1H).

N-(5-(4-(Benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)methanesulfonamide(28.0 mg, 56.1%, yellow solid) was prepared fromN-(5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)pyridin-3-yl)methanesulfonamide(45.0 mg, 0.105 mmol) and phenylboronic acid (15.4 mg, 0.126 mmol),2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (10.0 mg, 0.0210mmol), Pd(OAc)₂ (2.36 mg, 0.0105 mmol) and K₂CO₃ (43.6 mg, 0.315 mmol)by the methods described for the preparation of5-(4-(benzylamino)-5-phenylpyrrolo[1,2-b]pyridazin-2-yl)-N-(tert-butyl)pyridine-3-sulfonamidein Example 1. The residue was purified by preparative HPLC (Condition 8as described in general methods). LCMS (Condition 1): retention time2.05 min, [M+1]=470.2. HPLC (Condition 15): retention time=17.90 min,purity 98.87%. ¹H NMR (400 MHz, DMSO-d₆) δ 3.11 (s, 3H), 4.54 (d, J=5.6Hz, 2H), 5.56 (dd, J=5.2 Hz, J=5.6 Hz, 1H), 6.31 (s, 1H), 6.74 (d, J=2.8Hz, 1H), 7.26-7.52 (m, 10H), 7.81 (d, J=2.8 Hz, 1H), 8.14 (dd, J=2.0 Hz,J=2.4 Hz, 1H), 8.51 (d, J=2.4 Hz, 1H), 8.86 (d, J=2.0 Hz, 1H), 10.09 (s,1H).

Example 5 Diethyl5,5′-(4-(benzylamino)pyrrolo[1,2-b]pyridazine-2,5-diyl)dinicotinate

To the solution of4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl(1,3,2-dioxaborolan-2-yl))-1,3,2-dioxaborolane(1.54 g, 6.09 mmol) and tricyclohexylphosphonium tetrafluoroborate(0.112 g, 0.304) in 1,4-dioxane (20 mL) at ambient temperature was addedpotassium acetate (1.71 g, 17.4 mmol) and the reaction mixture waspurged with nitrogen gas for 10 min. The reaction mixture was heated to80° C. Pd₂(dba)₃ (0.199 g, 0.217 mmol) was added to the reaction mixtureand again nitrogen was passed through for the next 10 min at 80° C. Thereaction mixture was heated to 90° C. and a solution of ethyl5-bromonicotinate (1.00 g, 4.35 mmol) in 1,4-dioxane (5 mL) was added.The resulting mixture was stirred at 100° C. for 16 h. The reactionmixture was allowed to cool to ambient temperature, filtered throughCELITE and the filtrate was concentrated under reduced pressure toobtain ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate(1.5 g). The residue was taken to the next step without furtherpurification. LCMS (Condition 5): retention time 0.52 min, [M+1]=196.1.¹H NMR (400 MHz, DMSO-d₆) δ 1.16 (s, 12H), 1.35 (t, J=7.2 Hz, 3H), 4.36(q, J=7.2 Hz, 2H), 8.43 (dd, J=1.6 Hz J=2.0 Hz, 1H), 8.95 (d, J=1.6 Hz,1H), 9.16 (br s, 1H).

To a stirred solution ofN-benzyl-2,5-dichloropyrrolo[1,2-b]pyridazin-4-amine (300 mg, 1.03 mmol)and ethyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate (427mg, 1.54 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was addedPd(TPP)₂Cl₂ (36.0 mg, 0.0510 mmol) followed by NaHCO₃ (259 mg, 3.08mmol). The resulting suspension was purged with nitrogen for 5 minutesand irradiated in microwave at 110° C. for 45 min. The reaction mixturewas allowed to cool to room temperature and diluted with water. Thereaction mixture was then extracted with EtOAc. The combined organicextracts were washed with brine, dried over anhydrous Na₂SO₄, filteredand concentrated under reduced pressure. The residue was purified bycombiflash (REDISEP®, silica gel, 12 g, 15% EtOAc/hexanes) and theresulting mixture was further purified by preparative HPLC (Condition 13as described in general methods) to afford ethyl5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)nicotinate (120mg, 28.4%) and diethyl5,5′-(4-(benzylamino)pyrrolo[1,2-b]pyridazine-2,5-diyl)dinicotinate(60.0 mg, 11.1%) as a light yellow solid.

Ethyl5-(4-(benzylamino)-5-chloropyrrolo[1,2-b]pyridazin-2-yl)nicotinate: LCMS(Condition 1): retention time 2.51 min, [M+1]=407.2. HPLC (Condition14): retention time=19.12 min, purity 99.95%. ¹H NMR (400 MHz, DMSO-d₆)δ 1.37 (t, J=7.2 Hz, 3H), 4.41 (q, J=7.2 Hz, 2H), 4.74 (d, J=6.0 Hz,2H), 6.29 (s, 1H), 6.77 (d, J=2.8 Hz, 1H), 7.22-7.29 (m, 2H), 7.35-7.49(m, 4H), 7.79 (d, J=2.8 Hz, 1H), 8.65 (dd, J=2.0 Hz, J=2.4 Hz, 1H), 9.13(d, J=2.0 Hz, 1H), 9.26 (d, J=2.4 Hz, 1H).

5,5′-(4-(Benzylamino)pyrrolo[1,2-b]pyridazine-2,5-diyl)dinicotinate:LCMS (Condition 1): retention time 2.45 min, [M+1]=522.2. HPLC(Condition 14): retention time=17.61 min, purity 99.07%. ¹H NMR (400MHz, DMSO-d₆) δ 1.35 (t, J=7.2 Hz, 3H), 1.39 (t, J=6.8 Hz, 3H), 4.39 (q,J=7.2 Hz, 2H), 4.42 (q, J=6.8 Hz, 2H), 4.57 (d, J=5.6 Hz, 2H), 6.21 (t,J=5.6 Hz, 1H), 6.44 (s, 1H), 6.94 (d, J=2.8 Hz, 1H), 7.24-7.45 (m, 5H),7.95 (d, J=2.8 Hz, 1H), 8.32 (dd, J=2.0 Hz, J=2.4 Hz, 1H), 8.72 (dd,J=2.0 Hz, J=2.4 Hz, 1H), 8.96 (d, J=2.4 Hz, 1H), 9.02 (d, J=2.0 Hz, 1H),9.15 (d, J=2.0 Hz, 1H), 9.32 (d, J=2.4 Hz, 1H).

Example 6

Example 6 was synthesized via the procedures described above forExample 1. LC/MS data was collected using method mentioned in the table,and the molecular mass determined by MS(ES) by the formula m/z. Both theretention time and MS data for Example 6 was listed in Table.

LC/MS Rt (min) Ex Method No. Structure Name ¹H NMR M + H 6

5-(4-(Benzylamino)- 5-(3-fluorophenyl) pyrrolo[1,2-b]pyridazin-2-yl)-pyridine-3- sulfonamide ¹H NMR (400 MHz, DMSO-d₆) δ 4.60 (d, J =5.6 Hz, 2 H), 5.75 (t, J = 5.6 Hz, 1 H), 6.50 (s, 1 H), 6.82 (d, J = 2.8Hz, 1 H), 7.12-7.17 (m, 1 H), 7.26-7.48 (m, 10 H), 7.89 (d, J = 2.8 Hz,1 H), 8.75 (dd, J = 2.0 Hz, J = 2.4 Hz, 1 H), 9.04 (d, J = 2.4 Hz, 1 H),9.35 (d, J = 2.0 Hz, 1 H). 2.77 Condition 7 474.0

UTILITY

In general, compounds of the present invention, such as particularcompounds disclosed in the preceding examples, have been shown toinhibit the K_(v)1 subfamily of voltage-gated K⁺ channels (for example,by displaying % inhibition values ≧14%, preferably ≧30%, more preferably≧40%, even more preferably ≧50%, at 0.3 micromolar concentration in anassay such as those set forth below). By displaying activity asinhibitors of the K_(v)1 subfamily of voltage-gated K⁺ channels,compounds of the present invention are expected to be useful in thetreatment of human diseases associated with the K_(v)1 subfamily ofvoltage-gated K⁺ channels.

Assays to determine the degree of activity of a compound as an I_(Kur)inhibitor are well known in the art and are described in references suchas J. Gen. Physiol., 101(4):513-543 (April 1993), and Br. J. Pharmacol.,115(2):267-274 (May 1995).

Assays to determine the degree of activity of a compound as an inhibitorof other members of the K_(v)1 subfamily are also well known in the art.For example, inhibition of K_(v)1.1, K_(v)1.2 and K_(v)1.3 can bemeasured using procedures described by Grissmer, S. et al., Mol.Pharmacol., 45(6):1227-1234 (June 1994); inhibition of K_(v)1.4 can bemeasured using procedures described by Petersen, K. R. et al., PflugersArch., 437(3):381-392 (February 1999); inhibition of K_(v)1.6 can bemeasured using procedures described by Bowlby, M. R. et al., J.Neurophysiol., 73(6):2221-2229 (June 1995); and inhibition of K_(v)1.7can be measured using procedures described by Kalman, K. et al., J.Biol. Chem., 273(10):5851-5857 (Mar. 6, 1998).

Examples 1-6, as shown in Table 2, were assayed for block of I_(Kur)current in patch clamped mammalian L-929 cells which were injected withhuman K_(V) 1.5 mRNA and stably expressed I_(Kur) protein (as describedin the references described below). Inhibition data at 0.3 mMconcentration for the Examples are shown in Table 2.

-   1. Synders, D. J. et al., “A rapidly activating and slowly    inactivating potassium channel cloned from human heart: functional    analysis after stable mammalian cell culture expression”, J. Gen.    Physiol., 101:513-543 (1993).-   2. Zhou, Z. et al., “Block of HERG potassium channels by the    antihistamine astemizole and its metabolites desmethylastemizole and    norastemizole”, J. Cardiovasc. Electrophysiol., 10(6):836-843    (1999).

TABLE 2 Percentage inhibition of Kv1.5 in Example No. L-929 cells at 0.3μM 1 99 2 37 3 98 4 98 5 34 6 95

Compounds within the scope of the present invention inhibit the K_(v)1subfamily of voltage-gated K⁺ channels, and as such are believed to beuseful in the treatment and/or prevention of various disorders: cardiacarrhythmias, including supraventricular arrhythmias, atrial arrhythmias,atrial flutter, atrial fibrillation, complications of cardiac ischemia,and use as heart rate control agents, including maintaining normal sinusrhythm; angina pectoris including relief of Prinzmetal's symptoms,vasospastic symptoms and variant symptoms; gastrointestinal disordersincluding reflux esophagitis, functional dyspepsia, motility disorders(including constipation and diarrhea), and irritable bowel syndrome;disorders of vascular and visceral smooth muscle including asthma,chronic obstructive pulmonary disease, adult respiratory distresssyndrome, peripheral vascular disease (including intermittentclaudication), venous insufficiency, impotence, cerebral and coronaryspasm and Raynaud's disease; inflammatory and immunological diseaseincluding inflammatory bowel disease, rheumatoid arthritis, graftrejection, asthma. chronic obstructive pulmonary disease, cysticfibrosis and atherosclerosis; cell proliferative disorders includingrestenosis and cancer (including leukemia); disorders of the auditorysystem; disorders of the visual system including macular degenerationand cataracts; diabetes including diabetic retinopathy, diabeticnephropathy and diabetic neuropathy; muscle disease including myotoniaand wasting; peripheral neuropathy; cognitive disorders; migraine;memory loss including Alzheimer's and dementia; CNS mediated motordysfunction including Parkinson's disease, and ataxia; epilepsy; andother ion channel mediated disorders.

As inhibitors of the K_(v)1 subfamily of voltage-gated K⁺ channelscompounds of the present invention are believed to be useful to treat avariety of further disorders including resistance by transplantation oforgans or tissue, graft-versus-host diseases brought about by medullaossium transplantation, rheumatoid arthritis, systemic lupuserythematosus, Hashimoto's thyroiditis, multiple sclerosis, myastheniagravis, type I diabetes uveitis, juvenile-onset or recent-onset diabetesmellitus, posterior uveitis, allergic encephalomyelitis,glomerulonephritis, infectious diseases caused by pathogenicmicroorganisms, inflammatory and hyperproliferative skin diseases,psoriasis, atopical dermatitis, contact dermatitis, eczematousdermatitises, seborrhoeis dermatitis, Lichen planus, Pemphigus, bullouspemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides,erythemas, cutaneous eosinophilias, Lupus erythematosus, acne, Alopeciaareata, keratoconjunctivitis, vernal conjunctivitis, uveitis associatedwith Behcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer Scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns and leukotriene B4-mediateddiseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjögren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia osses dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastatis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augention ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are suspected antiarrhythmicagents which are useful in the prevention and treatment (includingpartial alleviation or cure) of arrhythmias. As inhibitors of K_(v)1.5,compounds within the scope of the present invention are particularlyuseful in the selective prevention and treatment of supraventriculararrhythmias such as atrial fibrillation, and atrial flutter. By“selective prevention and treatment of supraventricular arrhythmias” ismeant the prevention or treatment of supraventricular arrhythmiaswherein the ratio of the prolongation of the atrial effective refractoryperiod to the prolongation of the ventricular effective refractoryperiod is greater than 1:1. This ratio can also be greater than 4:1,even greater than 10:1. In addition, the ratio may be such thatprolongation of the atrial effective refractory response period isachieved without significantly detectable prolongation of theventricular effective refractory period.

In addition, the compounds within the scope of the present inventionblock I_(Kur), and thus may be useful in the prevention and treatment ofall I_(Kur)-associated conditions. An “I_(Kur)-associated condition” isa disorder which may be prevented, partially alleviated or cured by theadministration of an I_(Kur) blocker. The K_(v)1.5 gene is known to beexpressed in stomach tissue, intestinal/colon tissue, the pulmonaryartery, and pancreatic beta cells. Thus, administration of an I_(Kur)blocker can provide useful treatment for disorders such as: refluxesophagitis, functional dyspepsia, constipation, asthma, and diabetes.Additionally, K_(v)1.5 is known to be expressed in the anteriorpituitary. Thus, administration of an I_(Kur) blocker can stimulategrowth hormone secretion. I_(Kur) inhibitors can additionally be usefulin cell proliferative disorders such as leukemia, and autoimmunediseases such as rheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the formula (I), (Ia), or compoundsexemplified in the examples. Other therapeutic agents such as thosedescribed below may be employed with the inventive compounds in thepresent methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

Dosage and Formulation

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula (I), (Ia), orcompounds exemplified in the examples, or salts thereof capable ofpreventing or treating one or more of the aforementioned disorders in anamount effective therefor, and a pharmaceutically acceptable vehicle ordiluent. The compositions of the present invention may contain othertherapeutic agents as described below, and may be formulated, forexample, by employing conventional solid or liquid vehicles or diluents,as well as pharmaceutical additives of a type appropriate to the mode ofdesired administration (for example, excipients, binders, preservatives,stabilizers, flavors, etc.) according to techniques such as those wellknown in the art of pharmaceutical formulation.

The compounds of the formula (I), (Ia), or compounds exemplified in theexamples, may be administered by any suitable means, for example,orally, such as in the form of tablets, capsules, granules or powders;sublingually; bucally; parenterally, such as by subcutaneous,intravenous, intramuscular, or intrasternal injection or infusiontechniques (e.g., as sterile injectable aqueous or non aqueous solutionsor suspensions); nasally such as by inhalation spray; topically, such asin the form of a cream or ointment; or rectally such as in the form ofsuppositories; in dosage unit formulations containing non toxic,pharmaceutically acceptable vehicles or diluents. The present compoundsmay, for example, be administered in a form suitable for immediaterelease or extended release. Immediate release or extended release maybe achieved by the use of suitable pharmaceutical compositionscomprising the present compounds, or, particularly in the case ofextended release, by the use of devices such as subcutaneous implants orosmotic pumps. In the case where the compounds of formula (I), (Ia), orcompounds exemplified in the examples, are being administered to preventor treat arrhythmias, the compounds may be administered to achievechemical conversion to normal sinus rhythm, or may optionally be used inconjunction with electrical cardioconversion.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula (I), (Ia), or compounds exemplified inthe examples, may also be delivered through the oral cavity bysublingual and/or buccal administration. Molded tablets, compressedtablets or freeze-dried tablets are exemplary forms which may be used.Exemplary compositions include those formulating the present compound(s)with fast dissolving diluents such as mannitol, lactose, sucrose and/orcyclodextrins. Also included in such formulations may be high molecularweight excipients such as celluloses (AVICEL®) or polyethylene glycols(PEG). Such formulations may also include an excipient to aid mucosaladhesion such as hydroxy propyl cellulose (HPC), hydroxy propyl methylcellulose (HPMC), sodium carboxy methyl cellulose (SCMC), maleicanhydride copolymer (e.g., Gantrez), and agents to control release suchas polyacrylic copolymer (e.g., Carbopol 934). Lubricants, glidants,flavors, coloring agents and stabilizers may also be added for ease offabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitable nontoxic, parenterally acceptable diluents or solvents, such as mannitol,1,3 butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquefy and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders, including: other antiarrhythmic agents such as Class I agents(e.g., propafenone), Class II agents (e.g., carvadiol and propranolol),Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide andibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HTantagonists (e.g., sulamserod, serraline and tropsetron), anddronedarone; calcium channel blockers (both L-type and T-type) such asdiltiazem, verapamil, nifedipine, amlodipine and mybefradil;Cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors) such asaspirin, indomethacin, ibuprofen, piroxicam, naproxen, CELEBREX®, VIOXX®and NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide and tirofiban), P2Y12 antagonists (e.g.,clopidogrel, cangrelor, ticlopidine and CS-747), P2Y1 antagonists,thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-IIIinhibitors (e.g., dipyridamole) with or without aspirin; diuretics suchas chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, and spironolactone; anti-hypertensive agentssuch as alpha adrenergic blockers, beta adrenergic blockers, calciumchannel blockers, diuretics, renin inhibitors, ACE inhibitors, (e.g.,captropril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril,delapril, pentopril, quinapril, ramipril, lisinopril), A II antagonists(e.g., losartan, irbesartan, valsartan), ET antagonists (e.g.,sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), nitrates, and combinations of such anti-hypertensiveagents; antithrombotic/thrombolytic agents such as tissue plasminogenactivator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA),factor VIIa inhibitors, factor Xa inhibitors (such as razaxaban), XIainhibitors, thrombin inhibitors (e.g., hirudin and argatroban), PAI-1inhibitors (i.e., inactivators of tissue plasminogen activatorinhibitors), α2-antiplasmin inhibitors, streptokinase, urokinase,prourokinase, anisoylated plasminogen streptokinase activator complex,and animal or salivary gland plasminogen activators; anticoagulants suchas warfarin and heparins (including unfractionated and low molecularweight heparins such as enoxaparin and dalteparin); HMG-CoA reductaseinhibitors such as pravastatin lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522(a.k.a. rosuvastatin, or atavastatin or visastatin); othercholesterol/lipid lowering agents such as squalene synthetaseinhibitors, fibrates, and bile acid sequestrants (e.g., QUESTRAN®);antiproliferative agents such as cyclosporin A, TAXOL®, FK 506, andadriamycin; antitumor agents such as TAXOL®, adriamycin, epothilones,cisplatin and carboplatin; anti-diabetic agents such as biguanides(e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulins,meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride,glyburide and glipizide), biguanide/glyburide combinations (i.e.,GLUCOVANCE®), thiozolidinediones (e.g., troglitazone, rosiglitazone andpioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4 inhibitors;thyroid mimetics (including thyroid receptor antagonists) (e.g.,thyrotropin, polythyroid, KB-130015, and dronedarone); Mineralocorticoidreceptor antagonists such as spironolactone and eplerinone; growthhormone secretagogues; anti-osteoporosis agents (e.g., alendronate andraloxifene); hormone replacement therapy agents such as estrogen(including conjugated estrogens in premarin), and estradiol;antidepressants such as nefazodone and sertraline; antianxiety agentssuch as diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oralcontraceptives; anti-ulcer and gastroesophageal reflux disease agentssuch as famotidine, ranitidine, and omeprazole; anti-obesity agents suchas orlistat; cardiac glycosides including digitalis and ouabain;phosphodiesterase inhibitors including PDE III inhibitors (e.g.,cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosinekinase inhibitors; steroidal anti-inflammatory agents such asprednisone, and dexamethasone; and other anti-inflammatory agents suchas ENBREL®. The combinations can be co-formulated or in the form of kitspackaged to provide appropriate dosages for co-administration.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon particularembodiments, it will be obvious to those of ordinary skill in the artthat variations in the particular compounds and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A compound of formula (I)

or an enantiomer, diastereomer, tautomer, or salt thereof wherein: A is—(CH₂)_(m)—R², —CH(R²⁶)—R², —(CH₂)_(n-1)—O—R², —(CH₂)_(n-1)—NR²⁵—R²,—CH(R²⁶)—CO₂—R², or —(CH₂)_(n-1)—NR²⁵—CO²—R²; R¹ is C₁₋₁₀ alkylsubstituted with 1-2-OH, haloC₁₋₁₀ alkyl, C₂₋₁₂ alkenyl, or C₃₋₁₀cycloalkyl, wherein the cycloalkyl may be substituted with 0-2 R¹³; or Ris

any of which may be substituted with 0-2 R¹³; R² is phenyl, cyclopentyl,cyclohexyl, pyridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, piperidinyl,pyridinone, pyrrolidinyl, tetrahydropyrans, or thiazolyl, any of whichare substituted with 0-2 R^(2a); R^(2a), at each occurrence, isindependently H, —OH, F, Cl, Br, I, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀alkyl, C₃₋₁₀ cycloalkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4-to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to12-membered heteroaryl-C₁₋₁₀ alkyl, —CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴,—NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴, —(CH₂)_(m)—SO₂NR¹⁴R¹⁴,—(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂NR¹⁴R¹⁴, —NR¹⁴SO₂NR¹⁴R¹⁴,—CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴, —SO₂NR¹⁴COR¹⁴,—SO₂N¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴, —NR¹⁴CONR¹⁴R¹⁴,—C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴ or —NCOR¹⁴, wherein the alkyl,cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may besubstituted with 0-2 R^(14a), and the heteroaryl and heterocyclylconsist of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, S, or O; R³ is phenyl,pyridinyl, pyrimidinyl, or dihydropyran, or tetrahydropyran any of whichmay be substituted with 0-1 R^(3a); R^(3a) is halo, CN, NH₂,—O—C₁₋₃alkyl, or morpholinyl; R¹³, at each occurrence, is independentlyH, —OH, F, Cl, Br, I, CN, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, haloC₁₋₁₀ alkyl,C₃₋₁₀ cycloalkyl, C₂₋₁₂ alkenyl, C₂₋₁₂ alkynyl, C₆₋₁₀aryl, a 4- to12-membered heteroaryl, a 4- to 12-membered heterocyclyl, a 4- to12-membered heteroaryl-C₁₋₁₀ alkyl, —CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴,—NR¹⁴SO₂R¹⁴, ═O, —CONR¹⁴R¹⁴, —(CH₂)_(m)—SO₂NR¹⁴R¹⁴,—(CH₂)_(m)—NR¹⁴SO₂R¹⁴, —(CH₂)_(n)—NR¹⁴SO₂N¹⁴R¹⁴, —NR¹⁴SO₂NR¹⁴R¹⁴,CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴COR¹⁴, —SO₂NR¹⁴COR¹⁴,—SO₂NR¹⁴CONR¹⁴R¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, —NR¹⁴R¹⁴, —NR¹⁴CONR¹⁴R¹⁴,—C(═NOR¹⁴)NR¹⁴R¹⁴, —CONR¹⁴OR¹⁴ or —NCOR¹⁴, or OR¹⁴, wherein the alkyl,cycloalkyl, alkenyl, alkoxy, aryl, heteroaryl and heterocyclyl may besubstituted with 0-2 R^(14a), and the heteroaryl and heterocyclylconsist of carbon atoms and 1, 2, 3, or 4 heteroatoms independentlyselected from the group consisting of N, S, or O; R¹⁴, at eachoccurrence, is independently selected from hydrogen, C₁₋₁₀ alkyl, C₃₋₁₀cycloalkyl, C₆₋₁₀ aryl, a 4- to 12-membered heteroaryl or a 4- to12-membered heterocyclyl, wherein the alkyl, cycloalkyl, aryl,heteroaryl and heterocyclyl may be substituted with 0-3 R^(14a) and theheteroaryl and heterocyclyl consist of carbon atoms and 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO; or alternatively, two R¹⁴'s are taken together with the atoms towhich they are attached to form a cyclic ring, wherein the cyclic ringmay be substituted with 0-1 R^(14a) and optionally contain 1, 2, 3, or 4heteroatoms independently selected from the group consisting of N, S, orO; R^(14a), at each occurrence, is independently selected from F, Cl,Br, I, C₁₋₁₀ alkyl, haloC₁₋₁₀alkyl, C₆₋₁₀aryl, C₃₋₁₀cycloalkyl, a 4- to12-membered heteroaryl, a 4- to 12-membered heterocyclyl, F, Cl, Br, I,—CN, —NO₂, —CO₂R₂₆, —CO₂NR₂₄R₂₄, —OCF₃, —OR₂₅, ═O, —CONR²⁴R²⁴, —COR²⁴,—SO₂R²⁴, —NR²⁴R²⁴, —NR²⁴CO₂R²⁴, —SO₂NR²⁴R²⁴, or C₆₋₁₀arylC₁₋₁₀alkyl,wherein the heteroaryl and heterocyclyl consist of carbon atoms and 1,2, 3, or 4 heteroatoms independently selected from the group consistingof N, S, or O; R²⁴, at each occurrence, is independently selected fromhydrogen, C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl; R²⁵, at eachoccurrence, is independently selected from hydrogen, C₁₋₁₀alkyl,C₃₋₆cycloalkyl, or phenyl; R₂₆, at each occurrence, is independentlyselected from hydrogen, C₁₋₁₀alkyl, C₃₋₆cycloalkyl, or phenyl; m is 0 to4; n is 0 to 4; and n−1 is 2 to
 4. 2. The compound of claim 1, or saltthereof, wherein: one of R¹ or R^(1a) is C₁₋₁₀ alkyl substituted with1-2-OH, haloC₁₋₁₀ alkyl, or C₃₋₁₀ cycloalkyl, wherein the cycloalkyl maybe substituted with 0-2 R¹³; or

any of which may be substituted with 0-2 R¹³.
 3. The compound of claim2, or salt thereof, wherein: R¹³, at each occurrence, is independentlyH, —OH, F, Cl, Br, I, C₁₋₆ alkyl, C₁₋₆ alkoxy, haloC₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl, a 4- to 12-membered heteroaryl, wherein theheteroaryl is selected from tetrazolyl, —CN, —NO₂, —(CH₂)_(m)—SO₂R¹⁴,—NR¹⁴SO₂R¹⁴, —CONR¹⁴R¹⁴, —(CH₂)_(m)—SO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR¹⁴R¹⁴,—NR¹⁴CO₂N^(14b)R^(14b), NR¹⁴COR¹⁴, —NR¹⁴CO₂R¹⁴, —CO₂R¹⁴, or —NR¹⁴R¹⁴,wherein the alkyl, cycloalkyl, phenyl, and heteroaryl may be substitutedwith 0-2 R^(14a), and the heteroaryl and heterocyclyl consist of carbonatoms and 1, 2, 3, or 4 heteroatoms independently selected from thegroup consisting of N, S, or O; R¹⁴, at each occurrence, isindependently selected from hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, orphenyl, wherein the alkyl, cycloalkyl, and phenyl, may be substitutedwith 0-3 R^(14a); or alternatively, two R^(14b)'s are taken togetherwith the atoms to which they are attached to form a cyclic ring, whereinthe cyclic ring is morpholinyl, piperidinyl, or piperazinyl, and may besubstituted with 0-1 C₁₋₆alkyl; and R^(14a), at each occurrence, isindependently selected from F, Cl, Br, I, C₁₋₆ alkyl, haloC₁₋₆alkyl,phenyl, C₃₋₆cycloalkyl.
 4. The compound of claim 3, or salt thereof,wherein: A is —(CH₂)_(m)—R², —CH(R²⁶)—R², —(CH₂)_(n-1)—O—R²,—(CH₂)_(n-1)—NR²⁵—R², —CH(R²⁶)—CO₂—R², or —(CH₂)_(n-1)—NR²⁵—CO₂—R²; R²is phenyl, pyridinyl, pyrazinyl, pyrimidinyl, piperidinyl, orpyridinone, any of which are substituted with 0-2 R^(2a); and R^(2a), ateach occurrence, is independently H, —OH, F, C₁₋₆ alkyl, C₁₋₆ alkoxy, or6-SO₂NR¹⁴R¹⁴.
 5. The compound of claim 4, or salt thereof, wherein: R¹is C₁₋₁₀ alkyl substituted with 1-2-OH, haloC₁₋₁₀ alkyl, or C₃₋₁₀cycloalkyl, wherein the cycloalkyl may be substituted with 0-1 R¹³; orR¹ is

which may be substituted with 0-2 R¹³.
 6. The compound of claim 5, orsalt thereof, wherein: R¹³, at each occurrence, is independently H, C₁₋₆alkyl, or a 4- to 12-membered heteroaryl, wherein the heteroaryl isselected from tetrazolyl, —CN, —NR¹⁴SO₂R¹⁴, —CONR¹⁴R¹⁴, —SO₂NR¹⁴R¹⁴,—NR¹⁴CO₂NR¹⁴R¹⁴, —NR¹⁴CO₂NR^(14b)R^(14b), —NR¹⁴COR¹⁴, —CO₂R¹⁴, or—NR¹⁴R¹⁴, wherein the alkyl, and heteroaryl may be substituted with 0-2R^(14a); R¹⁴, at each occurrence, is independently selected fromhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenyl, wherein the alkyl,cycloalkyl, and phenyl, may be substituted with 0-3 R^(14a); or twoR^(14b)'s are taken together with the atoms to which they are attachedto form a cyclic ring, wherein the cyclic ring is morpholinyl, and maybe substituted with 0-1 C₁₋₆alkyl; and R^(14a), at each occurrence, isindependently selected from F, Cl, Br, I, C₁₋₆ alkyl, haloC₁₋₆alkyl,phenyl, or C₃₋₆cycloalkyl.
 7. The compound of claim 6, or salt thereof,wherein: A is —(CH₂)—R²; R² is phenyl,

any of which are substituted with 0-1 R^(2a); and R^(2a), at eachoccurrence, is independently H, —OH, F, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, or SO₂NR¹⁴R¹⁴.
 8. The compound of claim 7, or salt thereof,wherein: R³ is phenyl.
 9. The compound of claim 8, or salt thereof,wherein: R²⁴, at each occurrence, is independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl; R²⁵, at each occurrence,is independently selected from hydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, orphenyl; and R₂₆, at each occurrence, is independently selected fromhydrogen, C₁₋₆alkyl, C₃₋₆cycloalkyl, or phenyl.
 10. The compound ofclaim 9, or salt thereof, wherein: R¹³ at each occurrence, isindependently H, —CN, —NHSO₂R¹⁴, —CONH₂, —SO₂NR¹⁴R¹⁴,—NHCO₂NR^(14b)R^(14b), —NHCOR¹⁴, or —NH₂; and R¹⁴, at each occurrence,is independently selected from hydrogen, or methyl.
 11. A compound,enantiomer, diastereomer, or salt thereof, selected from the compoundsset forth in the examples.
 12. A pharmaceutical composition comprising atherapeutically effective amount of at least one compound of claim 1.13. The pharmaceutical composition of claim 12, further comprising atleast one other therapeutic agent.
 14. A method of treating arrhythmiacomprising administering to a patient in need thereof an effectiveamount of at least one compound of claim
 1. 15. A method of controllingheart rate comprising administering to a patient in need thereof aneffective amount of at least one compound of claim 1.